Implantable drug delivery devices

ABSTRACT

The invention relates generally to implantable drug delivery devices. Devices having a single drug chamber configuration, a divided drug chamber configuration and a compact dual-drug configuration are described. The devices have features to prevent clogging of the dispensing catheter and the creation of a local vacuum caused by the dispensing of the drug fluid. Also provided are features of a failsafe refilling process, automatic refill notification, and performance verification process. The divided drug chamber configuration enables frequent or continuous minute doses. A dual-drug chamber configuration uses self-locking refill containers to prevent mismatching between refill containers and drug chambers.

FIELD OF THE INVENTION

This invention relates to implantable and refillable drug deliverydevices with programmable features.

BACKGROUND

Drug delivery by means of injections, inhalation, trans dermal orswallowing pills or capsules generally results in varying drugconcentrations between dosings. Many diseases would be better treated ifthe therapeutic drug were given so as to obtain a more or less constantdrug level in the region of interest, especially if systemic drugconcentrations could be maintained at or near zero thereby minimizingside effects. Implantable drug delivery devices attempt to achieve thisby delivering small amounts of drug to a specific body cavity on afrequent basis. These delivery systems also are capable of protectingdrugs which are unstable in vivo and that would normally requirefrequent dosing intervals. Implantable drug delivery devices includepolymeric implants, implantable osmotic pump systems, and micro-pumps.

Polymeric implants, used extensively in controlled drug deliverysystems, include nondegradable polymeric reservoirs and matrices, andbiodegradable polymeric devices. In both cases the drug is released bydissolution into the polymer and then diffusion through the walls of thepolymeric device. The release kinetics of drugs from such systemsdepends on both the solubility and diffusion coefficient of the drug inthe polymer, the drug load, and, in the case of the biodegradablesystems, the in vivo degradation rate of the polymer. Examples ofpolymeric implants include simple cylindrical reservoirs of medicationsurrounded by a polymeric membrane and homogeneous dispersions of drugparticles throughout a solid matrix of nondegradable polymers.Biodegradable polymeric devices are formed by physically entrapping drugmolecules into matrices or microspheres. These polymers dissolve whenimplanted or injected and release drugs.

Another method for controlled prolonged delivery of a drug is the use ofan implantable osmotic pump. An osmotic pump is generally in a capsuleform having permeable walls that allow the passing of water into theinterior of the capsule containing a drug agent. The absorption of waterby the water-attracting drug composition within the capsule reservoircreates an osmotic pressure within the capsule to push the drug out ofthe capsule to the treatment site.

Implantable micro-pumps for drug delivery applications usually include apermeable membrane for controlled diffusion of a drug into the body froma suitable reservoir. Such devices are limited in application primarilysince the rate at which the drug is delivered to the body is completelydependent upon the rate of diffusion through the permeable membrane.With these devices the rate of drug delivery to the body may be affectedby differing conditions within the body. In addition, such systems makeno provision for the adjustment of the rate or time interval for drugdelivery, nor can the delivery rate be easily varied.

Although polymeric implants, osmotic pumps and micro-pumps may provide arelatively steady rate of drug release, some drugs are more effectivegiven in intervals. Implantable infusion pumps can be programmed todeliver drugs at very precise dosages and delivery rates. These pumpsmay have a feedback device that controls drug delivery according toneed. With the current development of electronics and miniaturization ofpumps and sensors, various vital signs can be monitored leading tofeedback systems such as for monitoring blood glucose levels anddelivering insulin when needed. The size of the pump depends on theamount of drug and the intended length of treatment. A barrier infeedback technology in using an implantable sensor is the problem ofbody proteins causing reduced sensitivity of the sensors, compromisingthe reliability of the sensor input.

There are many existing examples of implantable medical deviceapplications. Implantable insulin pump technology has been developedwith a goal of simulating the normal function of the pancreas by usingglucose sensors and the predictive mathematical models. The sensorswould assess the level of glucose in the blood and pass the informationto a control algorithm used in a microprocessor chip for causingappropriate action by the pump. Such a device delivers a dose of insulinthrough a catheter into a patient's abdominal cavity. According to onemanufacturer a disk-shaped pump weight of about 5 to 8 ounces whenfilled can hold an insulin supply adequate for several months and can berefilled with a syringe injection across abdominal tissue with batterylife lasting about eight to 13 years. This delivery system keeps theliver from secreting excess glucose (blood sugar) into the bloodstream.Current pump technology difficulties include blockage of the catheter,infection at the implantation site, as well as accidentally injectinginsulin refills into patient's abdomen instead of the pump reservoir. Atypical reservoir in an implantable pump is to be refilled every threemonths.

For pain relief, drug delivery devices include the SynchroMed, anexternally programmable implantable device for the administration ofmorphine sulfate to treat chronic pain, and the AlgoMed, designed totreat intractable pain in cancer patients. The AlgoMed device includes adrug reservoir implanted just under the skin of the abdomen, and a smallcatheter that delivers medicine to the spinal cord.

The treatment of glaucoma presents several strong challenges to drugdelivery implant technology due to the sensitivity of the eye whichtherefore requires more frequent and precise dosing of medication whilethe small anatomical space limits the size of an ocular implant device.The surface of the eye is a significant physical barrier to medicationsthat target intraocular treatment sites. Topical eye drops must be ableto permeate through the modified mucosal membrane that covers thecornea. Only a very small percentage (˜5%) of the eye drops actuallyreach the intraocular space. While drugs that are released rapidlyproduce a relatively rapid and high concentration in the body, followedby a sharp decline, it is preferable to have controlled-release systemsdeliver a drug at a slower rate for a longer period without manualapplication by patients. In many glaucoma treatments, two drugs areused; a first drug for reducing internal pressure inside the eye and asecond drug for reducing side effects. It is, therefore, desirable tohave a compact drug delivery device that can dispense two drugs withseparate dispensing controls.

To improve the reliability and safety of an implantable drug deliverypump device, it is desirable to have a pump with a catheter withpositive closing and a failsafe refilling process eliminating anypossibility of injecting drug into a body cavity during the refillingprocess, an automatic notification feature to alert the patient of theneed to take timely refilling action, as well as a process for verifyingthe performance of the pump. Preferably all of these desirable featurescan be achieved in an implantable drug delivery pump device using animplantable battery and without using an external controller.

To maintain a more constant rate of dispensing drug dosages, it isdesirable to have an implant pump capable of precisely delivering asmall amount of drug volume in the nano-liter range at each step ofpiston movement. It is desirable to infuse such minute dosages at timeintervals appropriate for sustaining drug efficacy while avoiding sideeffects. And it is desirable to have an automated refilling process toprevent the injection of drug outside the implant pump into body tissueswhile refilling the pump.

The following references describe implantable devices.

U.S. Pat. No. 6,497,699 by Ludvig, et al. describes a miniatureapparatus for the treatment of brain disorders. The apparatus is acombination of electronic and pharmacological devices placed and poweredentirely within the human body. A neuroprosthesis monitors theelectrical activity of a dysfunctioning brain area and delivers drugmolecules into the problem area. The apparatus includes a refillabledrug pump; a recording electrode for outputting an electrical signalcharacteristic of an electrical activity of the brain; and amicrocontroller to control the dispensing of the drug based on theelectrical signal. The timing and duration of the drug deliveries aredetermined by the feedback of the brain's own electrical activity. Theinvention describes an application of an implantable pump havingmultiple dispensing outlets for targeting different problem areas.However, no specific pump design is mentioned.

U.S. Pat. No. 5,832,932 by Elsberry, et al. discloses techniques andapparatus for infusing drugs into the brain to treat movement disorders.The invention employs an implantable pump and a catheter for infusingtherapeutic dosages of the one or more drugs into the brain at treatmentsites. A sensor for detecting the extent of the abnormal motor behaviormay be used in combination with the implantable pump and catheter. Thetherapeutic dosage is adjusted according to signal input of the sensorto decrease the abnormal motor behavior. According to the patent themethod is applicable to treat the symptoms of hypokinetic disorders,such as Parkinson's disease, and hyperkinetic disorders, such asAmyotrophic Lateral Sclerosis, Huntington's Disease, Ballism orDystonia. The application of drug delivery device for treating movementdisorder by brain infusion and the method of using a sensor for motionfeedback for adjusting drug dosage in an implantable pump device areincorporated by reference.

For ophthalmic applications, U.S. Pat. No. 6,976,982 by Santini, Jr., etal. and U.S. Pat. No. 7,455,667 by Uhland, et al. provide a flexiblemicrochip drug delivery device that attaches to the curved surface of aneyeball. The ophthalmic microchip device is in the form of an array ofdrug-containing microchips that are attached to a flexible supportinglayer conforming to the backside surface of an eye. Release of thecontents of each microchip reservoir is controlled by diffusion through,or disintegration of, the reservoir cap. The reservoir cap can be ananode made of thin film gold in electrical communication with a cathodein the device. When an electric potential of approximately 1 volt isapplied the reservoir cap is oxidized to facilitate its disintegration,exposing the reservoir contents to the surrounding fluid. Amicroprocessor is preprogrammed to release drug from specific reservoirsby directing power from a battery to specific reservoir caps. Oncereleased, the drug is in contact with the surface of the eye anddiffuses into the eye. The reservoir activation can also be conductedwirelessly by telemetry with electromagnetic or optical means. Anoptical means can use an ophthalmic laser to activate LED receivers inthe device. However, a potential problem with these devices is that thedissolved cap material is not removed and may even “re-solidify” whenthe power for dissolving the cap material is off.

The invention of U.S. Pat. No. 7,181,287 by Greenberg deals with retinastimulation by electrodes or by drug to enable vision in blind patientsor treatment of a chronic condition. Specifically it is directed to animplantable device to enable delivery of drugs to the retina forstimulating the retina. The drug delivery device is secured by a tack tothe retina at a desired location without damaging the retina and it isout of the field of vision from the lens to the retina. The device maybe a passive osmosis type in the form of a hollow flexible polymericpillow containing drug for slow release to deliver drugs throughmultiple orifices to the desired treatment sites. The device may also bean active pump type receiving drug from a reservoir transferred by apressure development device through a tube with the flow rate controlledby a micro-valve. The microvalve, the pressure development device andthe reservoir are attached to the sclera outside the eye under theconjunctiva for ease of refilling of the reservoir. Also by the sameauthor, U.S. Pat. No. 7,483,750 specifically discloses preferredposition of a retinal device and the connection between a devicereservoir and the retinal device for avoiding damaging to the retina.The retinal implant is implanted subretinally at the back of the eyenear the fovea between the photoreceptor cell layer and the retinalpigment epithelium. The conduit connects the retinal implant with thedrug reservoir transretinally through retinal incision and the vitreouscavity. The preferred retina incision is at a location near the front ofthe eye where there is no retina to avoiding damage to the nutrient richchoroid and disruption of the blood supply to the retina. These twopatents provide applications and suitable location of a drug deliverydevice for treatments of chronic eye conditions and indicate thefeasibility of separating the small-size drug pillow positioned insidethe retina layer from the larger size pump body positioned outside theeye. However, the patents do not address the mechanism of dispensing thedrug in controlled manner. The use of an implantable pump for treatingretinal diseases is incorporated by reference.

U.S. Pat. No. 6,077,299 by Adelberg, et al. deals with a non-invasivelyadjustable valve implant for the drainage of aqueous humor in glaucoma.The implant valve is a rotor-type device with the valve openingcontrollable by a magnetic field through an external instrument. Theglaucoma valve of the invention overcomes the excess absorption problemof a newly implanted pump in a treatment area, where the aqueous humoris readily absorbed into the Tenon's tissue overlying the implant.Excess absorption can cause the pressure within the eye to fall to anunacceptably low level damaging eyesight. A higher pressure set-pointcan be made in the implant valve for the first few days after surgery tominimize the risk of the complications. The implant valve can also beadjusted to compensate for changes due to partial occlusion of the inlettube by particulate matter and infiltration by body tissue. However, thevalve implant of this invention is not a pump for dispensing drug.Nevertheless, the patent shows that non-invasive adjustability isrequired for an implant device.

For ocular drug delivery, U.S. Pat. No. 3,618,604 by Ness discloses adrug-dispensing ocular insert to deliver drug to the eye over aprolonged period of time. The ocular insert is comprised of either aflexible body of polymeric material or a sealed container havingmembrane walls insoluble in tear liquid and having an imperforatesurface. The drug contained in the insert is diffused at a controlledrate through the polymeric material or the membrane walls to the eye ina therapeutically effective amount. The ocular insert is to be placed inthe cul-de-sac of the conjunctiva between the sclera of the eyeball andthe lower lid. The inserts depend on osmotic pressure difference tocontrol drug delivery and they are not personalized for individualneeds. Their diffusion rates are not changeable once installed. Animplant pump with programmable timed release is desirable and to enablemore varied applications.

U.S. Pat. No. 7,377,907 by Shekalim provides an insulin pump thatsupplies insulin in a pre-pressurized chamber through a flow controlvalve. Precise metering is achieved by a piezoelectric actuator. Theinsulin in the chamber is pressurized and dispensed by a piston, whichis driven by a biased spring. The device also includes a pressureregulator, a removable cartridge unit containing a pre-pressurized fluidreservoir, and an electronic package for the programming of basal rates.Nevertheless, patients with a portal device are at risk fortrans-cutaneous infections.

To ensure positive closure at the dispensing opening, U.S. Pat. No.5,997,527 by Gumucio, et al. provides a drug delivery capsule devicecomprising an osmotic-agent chamber having a semi permeable membranewall, a drug chamber attached with a slit valve, and a moveable pistonseparating the two chambers. Under an osmotic pressure created in theosmotic chamber, the piston pushes drug through the slit valve. Beingexposed to the body tissue environment the permeable membrane wall ofthe osmotic chamber wall allows body fluid to pass into the capsule byosmosis to create an osmotic pressure to drive the piston. The osmoticcapsule of this invention lacks active control for ensuring positiveclosing of the slit valve. In operation, the osmotic pressure varieswith the movement of the piston and the remaining quantity of the drugin the drug chamber. At one end, an excessive osmotic pressure can keepthe slit valve at open state with continuous dispensing with apossibility of over-dosing. At the other end, an insufficient osmoticpressure cannot drive the piston to open the slit valve resulting in nodrug being dispensed. This unreliable drug delivery due to lack ofactive control can cause discomfort and adverse side effects in thepatient.

On the use of two fluidic drug chambers, U.S. Pat. No. 5,607,418 byArzbaecher provides an implantable drug delivery device having adeformable dispensing chamber within a deformable reservoir chamber. Inthis configuration, the dispensing flow rate of the dispensing chamberis designed to be greater than the refilling flow rate from thereservoir chamber and that the reservoir chamber automatically refillsthe dispensing chamber following discharge of a dispensing portion ofthe fluidic drug. Because the dispensing rate is greater than therefilling rate across the internal valve between the two deformablechambers, a partial vacuum may be created in the two chambers resultingin a poorly controlled dispensing rate or interruption of the dispensingflow to the treatment site. The deformable dispensing chamber within adeformable reservoir chamber cannot ensure that the drug flow rate inand out of the dispensing chamber and the reservoir chamber are equal.

U.S. Pat. No. 4,883,467 by Franetzki addresses the problem of gasbubbles in pumping medication fluid in a conventional implantablemedication device using a reciprocating piston pump wherein themedication reservoir is typically under atmospheric pressure between 0.5and 1.0 bar. Gas bubbles may be generated in pumping the medicationfluid at below ambient pressure or during refilling of the medicationreservoir. In the reciprocating motion in the pump chamber a gas bubblewould be merely compressed and decompressed without being transportedout of the device, making the infusion performance of the deviceunreliable. This under-pressure pumping is less a problem in largerpumps having a displacement volume greater than 10 microliters. But theexistence of dead space in the pump chamber of a small pump iscompounded because the size of the dead space may be comparable to thesize of the displacement volume of the piston. In this case, pumpingmedication containing gas bubbles may become impossible particularly atthe lower limit of the under-pressure (0.5 bar). This patent provides animplantable medication device using a magnetized reciprocating pistonand a magnetic check valve for pumping medication fluid containing gasbubbles to achieve a satisfactory infusion rate such that the patientwould receive medication without interruption by the gas bubbles. Thepiston contains a magnetic material which can be driven by a magneticmeans to move the piston forward for dispensing and a separate magneticmeans for moving the piston backward. The magnetic check valve isnormally biased to block fluid flow.

Addressing the problem of gas bubble formulation, U.S. Pat. No.7,201,746 by Olsen provides an implantable therapeutic substancedelivery device having a piston pump with an anti-cavitation. The devicehas an inlet chamber and a pumping chamber. In the pumping chamber apiston having a permanent magnet is driven by the magnetic fieldscreated by two separate inductive coils which impart a reciprocatingmotion to the piston to pump fluid from the pumping chamber into anoutlet. In such a pump chamber the backflow of fluid from the inletchamber can decrease pressure in the pumping chamber causing gasses tocome out of solution when the pumping chamber is being filled with thefluid. The invention provides an anti-cavitation valve that isconfigured to open when the therapeutic substance inlet pressure exceedsthe inlet chamber pressure and to close when the inlet chamber pressureexceeds the therapeutic substance inlet pressure. The objective of theanti-cavitation valve is to prevent the pumping chamber pressure fromdecreasing below a predetermined low pressure level during pistonretraction and to enable more complete filling of the pumping chanterwhen the piston is retracted.

Both U.S. Pat. Nos. 4,883,467 and 7,201,746 utilize a magnetized pistondriven by magnetic forces and attempt to suppress gas bubble formationby using biased valve mechanisms to increase the pressure in their pumpchambers. However, without positive mechanical control of the piston,the piston movement under the magnetic forces depends on the pressurelevel in the pump chamber, which may vary in operation. Also, thecompressed gas bubbles inside the pump chamber may expand when releasedat the device exit at the treatment site. Furthermore, these deviceconfigurations inherently entrap gas pockets and allow for the existenceof dead space which is a major source of the pumping problem.

US Patent Application 20080287874 by Elmouelhi controls the dead volumeof a piston pump by using an adjustment screw. The infusion pump deviceis of a reciprocating magnetized pistontype driven by solenoid coils.Typical manufacturing tolerances in the production of the pumpcomponents may result in unwanted dead space in the pumping chamber. Thedead space includes space that the piston does not reach at the limit ofits forward movement that leads to trapped air bubbles not displacedduring the pumping strokes, the pumping volume of the piston may not beaccurate as the piston movement may result in the compression of the airbubbles rather than displacement of the fluid. The invention solves theproblem by adjusting the end position of the piston's forward strokewith an adjustment screw allowing for selective elimination of the deadvolume and precise adjustment of the fluid pumped. Similarly US PatentApplication 20080269682 by Kavazov et al. address the reservoir airbubble problems of a magnetized reciprocating piston pump by modifyingthe geometry of the plunger or the reservoir of the pump device. Invarious embodiments of the invention, a reservoir, a plunger head whichmoves within the reservoir, or both the reservoir and the plunger headare shaped to form a bubble trap region for trapping air bubbles so asto limit the presence of air bubbles in a fluidic medium expelled fromthe reservoir. Both of these patents recognize the existence of deadvolume due to the structure of its piston pump device and attempt tominimize the air bubble problems. However, a piston pump that eliminatesdead volume such that no air bubble problems exist would be preferable.

On refilling, U.S. Pat. No. 7,347,854 by Shelton, et al. relates to aprocess of refilling an implantable drug delivery device. The controllerin accordance with this invention is programmed to determine the volumeof the old drug remaining in the reservoir. The controller then monitorsthe subsequent delivery of the old drug to the patient to determine whenthe remaining old drug has been cleared from the device. Accordingly,the controller adopts a new dispensing profile for the drug refilledinto the reservoir. The process as described in this patent is limitedto the general practice of adding new drug after using up the originaldrug in the reservoir. No specific refill steps such as retracting apiston, closing a dispensing tip and using a passive syringe areaddressed. In fact, a programmable pump allows changing the dispensingprofile at any time depending on the need of a patient prior to using upthe existing drug in the reservoir.

An implantable drug delivery pump of U.S. Pat. No. 6,283,949 by Roordadiscloses a method of dispensing drug at a controllable rate from areservoir. The pump includes a reservoir, a dispensing chamber, acompressible dispensing tube attached to the dispensing chamber, and arotating-arm actuator for applying a compressive force onto thedispensing tube to deliver the drug through a catheter. The rotating-armactuator allows additional drug drawn into the dispensing tube from thereservoir, which can be refilled. A one-way intake valve is used and thereservoir can be refilled through a septum. In this method, rotationalactuator compressive force is used and the reservoir is limited to acircular configuration to accommodate the rotating arm. The patent doesnot address failsafe requirements for refilling a pump reservoir.

U.S. Pat. No. 4,784,646 by Feingold provides a subcutaneous deliverydevice for injecting drug to a local destination. The subcutaneousdelivery device is mainly a catheter having a self-sealing port at theinput end attached with an internal magnet and a valve at the outputend. The catheter device further includes a corresponding externalmagnet, separated from the internal magnet by the skin, as a locator formagnetically adapting to the internal magnet. The attraction between thetwo magnets, which are annular magnets of opposite polarities, canfacilitate positioning and stabilizing a syringe needle duringinjection. However, the syringe needle may still be inserted at wronglocation and the drug in the syringe be injected by pressing the plungerof the syringe, therefore, causing damage to body tissues. Furthermore,the valve at the dispensing end of the device cannot be positivelycontrolled for dosing as the internal pressure in the device may exceedthe self-dosing pressure of the valve.

U.S. Pat. No. 7,044,932 by Borchard, et al. provides an access templatefor locating the refill septum of an implant drug pump. The needleinsertion occurs without using radiological instruments for guidance.The access template comprises a denial surface, an access port, andtemplate labeling. The denial surface has a periphery with a locationdiameter and an alignment feature. The denial surface is configured toprevent penetration through a dermal layer into the implantable drugpump. Using labels of the same color in both the template labeling andthe needle labeling provides a means for ensuring the proper drug beingadministered but the system is not failsafe as negligence in matchingcolors may occur.

To locate an implantable pump for the purpose of refilling, U.S. Pat.No. 7,191,011 by Cantlon discloses the use of a port with lightemitters. The light emitters can be arranged in various geometric formsand colors. Also disclosed are energy emitters such as light emittingdiodes, edge emitting diodes, or VCSELs, and sonic emitters. Theconcepts as disclosed are not applicable for situations where light orsonic waves cannot be detected such as under the skull. Furthermore,U.S. Pat. No. 7,356,382 by Vanderveen describes a system and method forverifying that a particular fluid supply is connected to an infusionpump by means of an operator-induced pressure change. An upstreampressure sensor coupled to a fluid supply conduit provides pressuresignals to a processor. In a verification mode, the processor receivesthe pressure sensor signals in comparison with an operator-inducedpressure change in the conduit to verify that the particular fluidsupply is connected to the infusion pump. The processor also prompts theoperator to confirm the pressure change if the pressure change signal isnot detected within a predetermined time period. However, use of anoperator-induced pressure change is not fail-proof. An operator mayenter incorrect pressure values or connect the wrong drug supply with acorrect pressure signal. A fail-proof system is needed to eliminate apossibility of operator errors.

U.S. Pat. No. 7,212,863 by Strandberg uses a test magnet in a specifiedtime period for external activation of an implantable medical device,which can be externally programmed within the specified time period.When the magnet is taken away the implant device returns to the normalmode of operation. The use of test magnets is a simple means of externalcontrol of the operation of an implant device without involving acomplex programmable external controller. The method of using anexternal test magnet for activating an internal device is incorporatedby reference.

On programming features, U.S. Pat. No. 6,381,496 by Meadows, et al.provides context switching features for changing the operationalparameters of an implantable device. These features enable a patient tochange the current set of operational parameters to another set ofoperational parameters. The ability to change the current operationalparameter set (OPS) is accomplished by including memory circuitry withinthe implant device wherein a plurality of OPS's are stored. An OPSsetting can be manually activated and transmitted to the implant deviceto replace the current OPS. The patent provides programmable featuresfor changing operational parameter settings, but it does not addressrefill steps and failsafe features.

U.S. Pat. No. 5,814,015 by Gargano, et al. uses a software warning as afailsafe measure for preventing the infusion of a wrong drug. Aprocessor driven syringe pump for two syringes in a housing unit issuspended from an N pole. Its software provides a number of feedbackwarnings and alarms. The syringe plunger is driven into the syringebarrel by a motor operated by a failsafe feature against a short circuitin a drive circuit element feeding continuous current into the pumpmotor. A pusher assembly for the syringe includes a split nut that canbe rotated and released to enable proper positioning of the syringe. Thetwo pumps are jointly programmable and operable to allow the automaticstopping of a first pump and starting of a second pump for extendedsequential infusion. Although the warnings and the failsafe feature areprovided by the software against a short circuit they do not guaranteeprevention of the infusion of the wrong drug. An ideal failsafe featureshould provide a means for automatically preventing the refilling of adrug chamber with an incorrect drug.

On drive means for imparting a piston or plunger motion a pump device, apiezoelectric motor driven by electric pulses can be used. U.S. Pat. No.6,940,209 by Henderson provides a piezoelectric lead screw motor fordriving an assembly that contains a threaded shaft and a threaded nut.Subjecting the threaded nut to piezoelectric vibrations causes thethreaded shaft to simultaneously rotate and translate in the axialdirection. A drive product based on the concept called Squiggle motorhas been commercialized. The SQUIGGLE SQ-306 model is 10 mm in lengthand 4 mm in diameter, and achieves precision levels in the micron range.The motor's power efficiency enables long battery life, which is acritical factor for implanted medical devices. Its motor driver boardincluding ASIC, resonant inductors, Boost circuit and FWID diode can bepackaged into 10 mm×10 mm×1.5 mm size. The use of commercially availableSQUIGGLE motor is incorporated by reference.

US Patent Application 20080108862 by Jordan; Alain et al. describes animplantable device comprising a stepper motor for driving with anoscillator and an external controller for monitoring and correction ofthe performance of the device by passive telemetry. The displacement ofthe actuator is proportional to the number of pulses given to the motorcoils. The method requires the use of an antenna coil coupled with aRF-to-DC converter to convert received RF energy to a DC voltage.However, the antenna coil and the converter add to the size of animplantable pump. The use of stepper motor as a drive means isincorporated by reference.

Alternatively, a piston or a plunger in a pump device can be driven byinduction coils. U.S. Pat. No. 7,331,654 by Horsnell, et al. provides asolenoid valve mechanism using induction coils for controlling the flowof fluid through the valve. The valve mechanism includes a plungermember for axial reciprocation within a tubular member supporting anelectric coil for generating a magnetic field when an electric currentpasses through the coil. The plunger is made of an electromagneticmaterial and can be magnetized by a magnetic field. The reciprocatingmotion of the plunger is adapted to open or close a nozzle orifice forinjecting fluid drops on demand, such as on ink jet printerapplications. The patent provides an example of using induction coilsfor driving plunger movements for dispensing fluid. The use of inductioncoils as a drive means is incorporated by reference.

With the limitations of the current implantable infusion pumptechnology, it is an objective of the present invention to preventclogging at the catheter exit and the creation of a partial vacuuminside the delivery device. It is an objective to provide a failsaferefilling process and an automatic notification feature for the patientto take timely action. Additionally, it is another objective to providea drug chamber configuration to enable dispensing of minute precise drugvolumes at high frequency or at a continuous mode. It is anotherobjective to provide a compact drug delivery device to dispense twodrugs without mis-matching during the refilling process.

SUMMARY OF INVENTION

The present invention includes three drug delivery deviceconfigurations. The first is a single drug chamber configuration. Thesecond is a divided drug chamber configuration. And the third is acompact dual-drug configuration that can dispense two drugsindependently.

An implantable single-drug delivery pump device of this inventioncomprises a first chamber attached with a catheter and containing a drugfluid, a second chamber containing a filler fluid, and a pistonseparating the drug fluid and the filler fluid. The filler fluid, whichis inert to the drug fluid, is partially enclosed by a collapsible wall.The collapsible wall, which is represented by bellow wall, enables thefiller fluid to follow the movement of the piston in filling in thespace in the first chamber vacated by dispensing of the drug fluid. Forpositive-closing at the dispensing opening, a slit valve is attached tothe catheter. The slit valve closes upon retraction of the piston. Thepiston is controlled by a driver means for undergoing smallreciprocating motion at predetermined amplitude which does not allowdispensing of the drug but does prevent clogging at the slit valve.

The implant pump is refillable. The positioning of a syringe needle canbe facilitated by the attraction between a first magnet mounted on theseptum of the pump device and a magnet attached to the needle. Therefill syringe is of a passage type without having an active plunger.

With the needle inserted, the retraction or backward movement of thepiston draws the refill fluid from the syringe into the first chamber.Continuous retraction of the piston draws in the drug fluid from thesyringe to fill the first chamber while the catheter entrance remainsclosed by a negative pressure drop developed in the filling process.

The refilling process starts when an activation detector is activated.The two-way movement of the piston is controlled to enable repeatedopening and closing motions of the slit valve with a specified amplitudeand frequency for preventing clogging without dispensing the drug.

For verification of the pump performance the piston is attached with asecond magnet to enable measurement of the distance between the firstmagnet and the second magnet by an external magnetic proximity sensorpositioned across the skin. The piston can be driven by a piezoelectricmotor or a stepper motor with the use of a threaded rod for achievinglinear displacement of the piston. Such a driver means is controlled bya microprocessor and powered by an implantable battery contained insidethe pump device. Alternatively, a piston can be made of ferrite materialfor magnetization by induction coils installed in the pump housing. Theinduction coils may be powered and controlled by an external controller.

The control software in the microprocessor controller is programmed toprovide Dispensing Mode, Refilling Mode, Notification Mode andVerification-Calibration Mode.

An alternative implantable single-drug delivery device includes adivided drug chamber having a reciprocating piston and a follower forintermittent dispensing of drug dosages and a failsafe needle-activationfeature for automatic refilling of the drug chamber. Also provided are abellows-type and a soft-layer-type filler-fluid chamber containing aninert fluid to fill the space evacuated by the movement of the pistonand the follower to prevent forming a partial vacuum in the fluidchambers enabling reliable performance of the device.

A drug delivery device of the divided drug chamber configurationcomprises a divided internal fluid chamber containing a first fluid andan external fluid chamber containing a second fluid that is enclosedpartially by collapsible soft-layered walls. The internal fluid chamberis divided into a first compartment and a second compartment by a wallmounted with a one-way valve.

The first compartment has a piston connected to a driving means and thesecond compartment has a follower, which is in communication with themovement of the piston. The second fluid in the external chamber servesas a filler fluid in communication with the internal fluid chamber forfilling the spaces behind the piston and the follower. Both the pistonand the follower separate the second fluid from the first fluid.

The piston performs a reciprocating motion under the control of a motordriver which is preprogrammed. The piston is preferably driven by ahigh-resolution piezoelectric motor for a minimal advancement in themicrometer range per step. With a miniature piston size, the drug volumemay be dispensed in the nano-liter range per piston step. During theforward motion of the piston the one-way valve is forced to close andthe slit-valve at the end of the catheter is forced to open to dispensethe drug fluid. During the backward motion of the piston a partialvacuum is created in the first compartment that causes the one-way valveto open and allow the drug fluid from the second compartment to enterthe first compartment. Simultaneously, the forward and backwardmovements of the piston and the follower cause the filler fluid to flowin or out, respectively, from the spaces behind the piston and thefollower. When the drug fluid is completely dispensed, the back spacesof the piston and the follower are full of the filler fluid.

Refilling of the first chamber is accomplished by inserting a refillcontainer into the septum of the device to force the one-way valve tocontact the opposing catheter wall, causing the attached electrodeelements to activate the reciprocating motion of the piston. Thereciprocating motion draws in the refill fluid to fill both the firstcompartment and the second compartment while the catheter entranceremains closed by the one-way valve. Similarly, a small reciprocatingmotion may be performed without dispensing drug fluid after the pistonis retracted a predetermined distance enabling refill and battery lownotifications.

An implantable dual drug delivery system of this invention features twodrug chambers and the use of self-locking refill containers for failsaferefilling of drug fluids in the device.

A self-locking refill container utilizes a movable magnet valve and anorifice plate for locking and unlocking the flow of drug fluid insidethe container reservoir. For a matched refill container, the polarity ofits magnet valve creates an attraction force toward the magnet on theseptum of the drug chamber. The attraction force moves the magnet valveaway from the orifice plate to enable the flow of the drug fluid fromthe refill container reservoir into the drug chamber. For a mis-matchedcontainer, the polarity of the magnet valve creates a repelling forceaway from the magnet on the septum such that the magnet valve is movedto contact the orifice plate and block the drug flow.

Specifically a dual drug delivery device of the present invention has afirst drug chamber containing a first drug fluid, a second drug chambercontaining a second drug fluid and an external filler fluid chambercontaining filler fluid. Each drug chamber is divided by a wall having aone-way valve into a first compartment and a second compartment. Eachfirst compartment has a piston connected to a drive means and eachsecond compartment has a follower, which is in flow communication withthe movement of the piston. A small reciprocating motion may beperformed without dispensing drug fluid after the piston is retractedfor a predetermined distance for refill and battery low notifications.

The filler fluid chamber is attached externally to the drug chambers andit contains a filler fluid enclosed by collapsible soft layers. Thefiller fluid is for filling the space left by the movements of thepistons and the followers to prevent a partial vacuum inside the drugchambers that would hinder the movements of the pistons.

DESCRIPTION OF THE DRAWINGS

FIG. 1a is a front cross-section view of an implantable drug deliverypump device using a piezoelectric motor with a drug reservoir at fullstate.

FIG. 1b is a front cross-section view of the implantable drug deliverypump device of FIG. 1 a with the drug reservoir at empty state.

FIG. 2a is a side cross-section view of a refill container of thepresent invention using a slidable disc.

FIG. 2b is a side cross-section view showing insertion of the refillcontainer needle of FIG. 2a into the implantable drug delivery pumpdevice of FIG. 1 a.

FIG. 2c is a side cross-section view of a refill container of thepresent invention showing a collapsible bag at expanded full state.

FIG. 2d is a side cross-section view of a refill container of FIG. 2cshowing the collapsible bag at a collapsed state.

FIG. 3 is a front cross-section view of an implantable drug deliverypump device using a stepper motor.

FIG. 4a is a cross section view of an implantable drug delivery pumpdevice using induction coils with the drug reservoir at full state.

FIG. 4b is a cross section view of an implantable drug delivery pumpdevice of FIG. 4a using an external controller for refilling.

FIG. 5 is a control chart of operation modes of an implantable drugdelivery pump device of the present invention.

FIG. 6a is a front cross-section view of an implantable drug deliverydevice having a divided drug reservoir and a bellows-type filler-fluidchamber.

FIG. 6b is a top cross-section view of FIG. 6a showing cross-sectionareas of the first and the second fluid compartments.

FIG. 6c is a side cross-section view of the implantable drug deliverydevice of FIG. 6a showing a one-way check valve.

FIG. 7a is an enlarged cross-section view of a flap-type one-way valveof FIG. 6c with a refill container needle.

FIG. 7b is an isometric exposed view of FIG. 7 a.

FIG. 7c is an enlarged cross-section view of a plunger-type one-wayvalve not touched by a refill container needle.

FIG. 7d shows the plunger-type one-way valve of FIG. 7c being pushed bythe needle of the refill container against the electrode plate on thecatheter wall blocking the flow channel.

FIG. 8a is a side cross-section view of the implantable drug deliverydevice of FIG. 6c showing the second compartment of the drug reservoirfull with first fluid.

FIG. 8b shows the implantable drug delivery device of FIG. 8a with thesecond compartment of the drug reservoir full with filler fluid.

FIG. 8c shows the implantable drug delivery pump device of FIG. 8b witha refill container needle inserted and pressing against a contactswitch.

FIG. 8d shows the implantable drug delivery pump device of FIG. 8b witha refill container needle being removed from the one-way valve in thedrug reservoir.

FIG. 9a is a front cross-section view of an implantable drug deliverydevice attached with a softlayer filler-fluid chamber.

FIG. 9b is a side cross-section view of the implantable drug deliverydevice of FIG. 9a showing soft-layer filler-fluid chamber attached tothe housing wall of the device.

FIG. 9c is a B-B cross-section of FIG. 9b showing flow gaps for fillerfluid on housing walls.

FIG. 10a is a side cross-section view of the implantable drug deliverydevice of FIG. 9b showing the second compartment of the drug reservoirat full state.

FIG. 10b shows the implantable drug delivery device of FIG. 10a with thesecond compartment of the drug reservoir full of filler fluid.

FIG. 10c shows the implantable drug delivery device of FIG. 10b with arefill container needle inserted and pressing against a contact switch.

FIG. 10d shows the implantable drug delivery device of FIG. 10c with arefill container needle being removed at completion of refilling.

FIG. 11 is a control chart of operation modes of an implant infusiondevice of the present invention.

FIG. 12a is a front cross-section view of an implantable dual drugdelivery device with two dispensing valves at opposite sides of thedevice.

FIG. 12b is a top cross-section view A-A of FIG. 12 a.

FIG. 12c is a side cross-section view of the implantable infusion dualdrug delivery device of FIG. 12 a.

FIG. 13 is an enlarged cross-section view of the one-way valve of FIG.12c with a refill container needle inserted.

FIG. 14a is a side cross-section view of the implantable dual drugdelivery device as shown in FIG. 12c indicating the second compartmentof the first drug reservoir full with first fluid.

FIG. 14b shows the implantable dual drug delivery device of FIG. 13awith the second compartment of the first drug reservoir full with thefiller fluid.

FIG. 14c shows the implantable dual drug delivery device of FIG. 13bwith a refill container needle inserted and pressing against a contactswitch in the first catheter.

FIG. 14d shows the implantable dual drug delivery device of FIG. 13bwith a refill container needle being removed from the one-way valve inthe first drug reservoir.

FIG. 15a shows refill container of Drug A unlocked internally withmatched septum of Drug A.

FIG. 15b shows refill container of Drug B locked internally due tomix-matching with the septum of Drug A.

FIG. 16a is an implantable dual drug delivery device of FIG. 15b withthe refill container of Drug A unlocked internally when inserted intothe septum of Drug A.

FIG. 16b is an implantable dual drug delivery device of FIG. 16a withthe spent refill container removed from the septum upon completion ofrefilling.

FIG. 17a is an implantable dual drug device of FIG. 16a with the refillcontainer of Drug A internally locked as inserted into the septum ofDrug B.

FIG. 17b is an implantable dual drug delivery device of FIG. 17a withthe refill container of Drug B unlocked internally when inserted intothe septum of Drug B.

FIG. 17c is an implantable dual drug delivery device of FIG. 17b withthe spent refill container removed from the septum upon completion ofrefilling.

FIG. 18a is a front cross-section view of an implantable dual drugdelivery device with two drug chambers oriented in the same direction.

FIG. 18b is a cross-section view A-A of FIG. 18 a.

FIG. 19 is a control chart of operation modes of an implantable dualdrug delivery device of the present invention

DESCRIPTION OF THE INVENTION

In the following descriptions, implantable drug delivery pump device andinfusion pump are used interchangeably. First fluid and drug fluid areused interchangeably. Second fluid and filler fluid are usedinterchangeably. First chamber, drug chamber and drug reservoir are usedinterchangeably. Second chamber and filler fluid chamber are usedinterchangeably.

Further, the present invention relates to

1. An implantable drug delivery device comprising;

a. housing walls,

b. a first chamber supported by the housing walls having an outlet andcontaining a first fluid,

c. a piston positioned inside said first chamber, being driven inforward and backward motions by a drive means, said piston moves thefirst fluid toward the outlet when being driven forward by a divermeans,

d. a second chamber having a collapsible wall containing a second fluid,said second fluid being separated from the first fluid by said piston,said collapsible wall collapses as the second fluid moves in with saidpiston in response to the reduced volume of the first fluid in the firstchamber.

e. a drive means for imparting motion of the piston.

2. An implantable drug delivery device of [1] wherein said housing wallsand the collapsible wall are impermeable.

3. An implantable drug delivery device of [1] wherein said collapsiblewall contracts as the second fluid moves in with said piston during thedispensing of the first fluid and said collapsible wall expands as thesecond fluid moves back with said piston when the first chamber isrefilled with the first fluid.

4. An implantable drug delivery device comprising:

a. housing walls,

b. a first chamber supported by the housing walls having an outlet andcontaining a first fluid,

c. a piston positioned inside said first chamber, being driven inforward and backward motions by a drive means, said piston moves thefirst fluid toward the outlet when being driven forward by the divermeans,

d. a catheter having a base end and a dispensing end, said base endbeing attached to the outlet,

e. a positive-closing valve being attached to the dispensing end of saidcatheter, said positive-closing valve opens when the piston moves towardthe outlet and closes when the piston moves away from the outlet,

f. a septum being attached to the outlet, said septum being in flowcommunication with said first chamber and said catheter,

g. a drive means for imparting motion of said piston.

5. An implantable drug delivery device of [4], wherein saidpositive-closing valve is a slit valve of a cap of elastomeric materialshaving a cross-slit cut at the apex of the cap forming a plurality offlexible flappers, said slit valve being at a closed position when nopumping pressure is exerted by the piston.

6. A process for preventing clogging of the positive-closing valve of animplantable drug delivery device of [4] wherein said drive means beingcontrolled by a microprocessor, said microprocessor being programmed tomove the piston forward a first distance for dispensing the first fluidand then to move the piston backward a second distance to ensure theclosing of the self-sealing valve, said first distance being larger thanthe second distance by a value corresponding to a specified amount ofthe first fluid being dispensed.

7. A process for preventing clogging of the dispensing end of animplantable drug delivery device of [6] wherein said microprocessorprovides repeated motions of opening and closing of the positive-closingvalve by moving the piston forward and backward with a specifiedfrequency and a specified amplitude that is incapable of dispensing thefirst fluid.

8. A process for refilling an implantable drug delivery device of [4]comprising the steps of:

a. signaling a need to refill the first chamber by using the oscillationmotion of said piston with a detectable amplitude and frequency,

b. inserting the needle of a refill container containing the first fluidinto said septum,

c. retracting the piston away from the outlet by the drive means forcingthe positive-closing valve to the closed position and resulting inwithdrawing the refill fluid from the syringe into the first chamber.

9. An implantable drug delivery device of [4] including a second chamberwhich has a collapsible wall containing a second fluid. said secondfluid being separated from the first fluid by said piston, saidcollapsible wall contracts as the second fluid moves in with said pistonin response to the reduced volume of the first fluid in the firstchamber.

10. An implantable drug delivery device comprising;

a. housing walls,

b. a first chamber supported by the housing walls having an outlet andcontaining a first fluid,

c. a piston positioned inside said first chamber and being driven inforward and backward motions by a drive means, said piston moves thefirst fluid toward the outlet when being driven forward by a divermeans,

d. a septum, attached to the outlet, said septum being in flowcommunication with said first chamber and said catheter,

e. a first magnet attached to said septum and a second magnet attachedto said piston,

f. a drive means for imparting motion to the piston,

g. an IC control board supported by the housing walls, said IC controlboard includes a microprocessor, electrical circuits and is incommunication with said drive means,

h. an activation detector in communication with said first magnet and anelectrical circuit in the IC control board that converts a change ofmagnetic field surrounding the first magnet into a voltage output.

11. An implantable drug deliver) device of [10] wherein said electricalcircuit comprises Wheatstone bridge elements to convert the magneticfield into a voltage output for measuring the distance between the firstmagnet and the second magnet.

12. An implantable drug delivery device of [10] including a secondchamber which has a collapsible wall containing a second fluid, saidsecond fluid being separated from the first fluid by said piston, saidcollapsible wall contracts as the second fluid moves in with said pistonin response to the reduced volume of the first fluid in the firstchamber.

13. An implantable drug delivery device of [10] including a slit valvewhich is attached to the dispensing end of said catheter, said slitvalve opens when the piston moves toward the outlet and closes when thepiston moves away from the outlet.

14. An implantable drug delivery device of [10] including a secondmagnet which is attached to said piston and the distance between thefirst magnet and the second magnet being measurable by a magnetproximity sensor to determine the position of said piston in the firstchamber.

15. An implantable drug delivery device of [10] in which flow gaps beingcreated between the motor and the housing walls for the flow of thesecond fluid from the second chamber to the space behind the piston inthe first chamber.

16. An implantable drug delivery device of [1], [4] or [10] wherein saiddrive means is a threaded rod and a motor imparting the rotation of thethreaded rod, which causes forward and backward movements of the pistonin the axial direction of the threaded rod corresponding to rotationaldirections of the motor.

17. An implantable drug delivery device of [16] wherein said motor is apiezoelectric motor or a stepper motor.

18. An implantable drug delivery device of [1] or [4] wherein saidpiston is made of ferrite material and said drive means comprising apermanent magnet positioned at the outlet end of the first chamber and aset of induction coils being supported by the housing walls, saidinduction coils magnetizing the piston to move in forward and backwarddirections depending on the polarity of the magnetic field induced bythe induction coils responding to directions of electrical currentimposed on the induction coils.

19. An implantable drug delivery device of [18] wherein said inductioncoils are controlled by an external controller using telemetry tomonitor and change the operational parameters of said induction coils.

20. An implantable drug delivery device of [1] or [4] including an ICcontrol board in electrical communication with the drive means.

21. An implantable drug delivery device of [20] including a battery inelectrical communication with the IC control board.

22. An implantable drug delivery device of [18] wherein said pistonmoves toward the outlet position when the piston is magnetized with apolarity in the same polarity direction of the permanent magnet, andsaid piston moves away from the outlet position when said piston beingmagnetized with polarity in the opposite polarity direction of thepermanent magnet.

23. An implantable drug delivery device of [17] wherein saidpiezoelectric motor has a threaded rod which is in free-to-rotateengagement with said piston, said piston having a non-circularcross-section undergoing linear movement without rotation.

24. An implantable drug delivery device of [17] wherein said steppermotor having a threaded shaft, said piston having non-circularcross-section and inner threads which are engaged with the threadedshaft, said piston moves in the axial direction of the threaded shaftwhen the stepper motor is activated.

25. A refill container for refilling an implantable drug delivery devicecomprising:

a. a tubular housing with inner wall surface having first opening andsecond opening, said tubular housing containing a drug fluid,

b. a needle being attached to the second opening and being in flowcommunication with the drug fluid,

c. a disc situated inside said tubular housing being in slidable sealingfit with inner wall surface, said disc not accessible from outside thehousing and being only movable following the flow direction toward theneedle when the drug fluid being drawing out of the housing through theneedle, said disc being exposing to ambient pressure through the firstopening.

26. A refill container for refilling an implantable drug delivery devicecomprising:

a. a collapsible pouch containing a drug fluid having flexible film wallfastened to a top plate having an exit opening, said film wall beingcollapsible when the drug fluid is drawn through the exit opening,

b. a needle being attached to the exit opening of the top plate andbeing in flow communication with the drug fluid.

27. A refill container for refilling an implantable drug delivery deviceof [26] including an external tubular housing wall, separate from thecollapsible pouch and forming a gap between the external housing walland the flexible film wall of said collapsible pouch, said gappreventing the pouch from being collapsed by a deflection of the housingwall causing dispensing of drug fluid.

28. A refill container for refilling an implantable drug delivery deviceof [26] including an external tubular housing wall, whose deflectiondoes not cause contraction of said collapsible pouch and forcing thedispensing of the drug fluid.

29. A refill container for refilling an implantable drug delivery deviceof [25], [26], [27] or [28] including an attached magnet surrounding theneedle.

30. An implantable drug delivery device comprising;

a. housing walls,

b. an internal fluid chamber, containing a first fluid, is supported byhousing walls and is divided into a first compartment and a secondcompartment by a wall having a one-way valve, the first compartmenthaving an outlet and a piston and the second compartment having afollower which is in communication with the movement of the piston,

c. an external fluid chamber containing a second fluid is supported byhousing walls and is enclosed partially by a collapsible wall, saidsecond fluid being separated from the first fluid by the piston and thefollower, said collapsible wall contracts as the second fluid moves inwith said piston in respond to the reduced volume of the first fluid inthe first chamber.

d. a drive means for imparting forward and backward movements of thepiston, said forward movement for moving the first fluid toward theoutlet and said backward movement for moving the first fluid away fromthe outlet.

31. An implantable drug delivery device of [30] wherein the forwardmovement of said piston causes the contraction of the collapsible walland the backward movement of said piston causes the expansion of thecollapsible wall.

32. An implantable drug delivery device of [30] wherein said walls ofthe internal chamber and the external chamber are impermeable to fluidspresent in an operating environment.

33. An implantable drug delivery device of [30] wherein said one-wayvalve closes when the piston moves toward the outlet and the one-wayvalve opens when the piston moves away from the outlet causing the firstfluid to flow from the second compartment into the first compartment.

34. An implantable drug delivery device system comprising:

a. a refill container comprising housing walls, a reservoir containingfirst fluid and a needle,

b. an internal fluid chamber containing first fluid, said internal fluidchamber being divided by a wall having a one-way valve into a firstcompartment having a piston and a second compartment having a follower,

c. an outlet having opposing walls forming a flow channel incommunication with said first compartment, said opposing walls can beforced to contact each other to block the flow of the first fluid byinsertion of the needle of said refill container.

d. a drive means for imparting motion of the piston.

35. An implantable drug delivery device system of [34] having anexternal fluid chamber, containing a second fluid which is enclosedpartially by collapsible walls, said second fluid being separated fromsaid first fluid by the piston and the follower and fills the space leftby the movements of the piston and the follower.

36. An implantable drug delivery pump device system of [34] having aseptum attached with a first magnet for positioning the needle of therefill container for insertion into the septum.

37. An implantable drug delivery device system of [34] wherein saidoutlet is attached with a catheter having a positive closing valvemounted at the dispensing tip, said valve opens when the piston movestoward the outlet and closes when the piston moves away from the outlet.

38. An implantable drug delivery device system of [34] wherein the firstfluid in said refill container is drawn into the internal fluid chamberby moving the piston away from the outlet.

39. An implantable drug delivery device system comprising:

a. a refill container comprising housing walls, a reservoir containing arefill fluid and a needle,

b. an internal chamber containing a first fluid and having an outlet anda piston, said outlet having opposing walls forming a flow channel forthe flow of the first fluid,

c. a septum being attached to the outlet of said internal chamber, saidseptum having a plunger for being pushed by the needle of said refillcontainer to block the flow channel of the outlet.

40. An implantable drug delivery device system comprising:

a. a refill container comprising housing walls, a reservoir containing arefill fluid and a needle,

b. an internal chamber containing a first fluid and having an outlet anda piston, said outlet having opposing walls forming a flow channel forthe flow of the first fluid,

c. a drive means for imparting forward and backward movements of thepiston, said forward movement for moving the first fluid toward theoutlet and said backward movement for moving the first fluid away fromthe outlet.

d. a contact switch in electrical communication with said drive means,said contact switch being activated by the insertion of the needle ofsaid refill container activating the movement of the piston.

41. An implantable drug delivery device system of [40] wherein saidcontact switch having opposing electrode plates with each electrodeplate being attached to said opposing walls of said outlet, and saidopposing walls can be forced to contact each other thereby blocking theflow of the first fluid through the outlet, and said movement of thepiston causing the flow of the first fluid from the refill container tothe internal fluid chamber.

42. An implantable drug delivery device system of [40] wherein saidcontact switch being formed by a stationary electrode plate and amovable electrode plate, said movable electrode plate being attached toa plunger which is spring loaded against a partition wall dividing apiston chamber and a reservoir chamber.

43. An implantable drug delivery device system of [40] having anexternal fluid chamber containing a second fluid that is enclosedpartially by collapsible walls, said second fluid being separated fromsaid first fluid by the piston and fills the space left by the movementof the piston.

44. An implantable drug delivery device system of [40] having a septumattached with a first magnet for positioning the refill container forinsertion into the septum.

45. An implantable drug delivery device system of [40] wherein the firstfluid in said refill container being drawn into the internal fluidchamber by moving the piston away from the outlet.

46. An implantable drug delivery device of [30], [34] or [40] whereinsaid drive means is a threaded rod and a motor imparting the rotation ofthe threaded rod, which causes forward and backward movements of thepiston in the axial direction of the threaded rod corresponding to therotational direction of the motor.

47. An implantable drug delivery device of [30], [34] or [40] whereinsaid motor is a piezoelectric motor comprising a threaded rod andpiezoelectric plates with one end forming a threaded-nut configurationand, said threaded rod rotates when said piezoelectric plates being inpiezoelectric vibration.

48. An implantable drug delivery device of [30], [34] or [40] whereinsaid internal fluid chamber having two parallel sidewalls and one ofsaid sidewalls is attached with said external fluid chamber having saidcollapsible walls containing the second fluid, which fills the spaceleft by the movements of the piston and the follower.

49. A process of ensuring positive-closing of the slit valve of animplantable drug delivery device of [30], [34] or [40] wherein saiddrive means is controlled by a microprocessor, said microprocessor beingprogrammed to move the piston forward for a first distance to dispensethe first fluid and then to move the piston backward for a seconddistance to ensure the closing of the self-sealing valve, said firstdistance being larger than the second distance by a value correspondingto a specified amount of the first fluid being dispensed.

50. A process of refilling an implantable drug delivery device of [30],[34] or [40] comprising steps of:

a. inserting a refill container containing first fluid into said septum,

b. retracting the piston away from the outlet by the drive meansresulting in withdrawing the refill fluid from the refill container intothe first chamber.

51. A process for refilling an implantable drug delivery device of [50]wherein the refill container is of the passive type having no plungerfor manually injecting first fluid into said first chamber.

52. A process of refilling an implantable drug delivery device of [50]or [51] including a step of signaling a need to refill the first chamberby using the reciprocating motion of said piston with a detectableamplitude and frequency,

53. A process of verifying the movement of a follower in a drug chamberof an implantable drug delivery device of [36] and [44] including asecond magnet being attached to the follower and measuring the distancebetween the second magnet and the first ring magnet at the septum by amagnet proximity sensor.

54. An implantable drug delivery device comprising a drug fluid chamber,a reciprocating piston and a battery for powering the reciprocatingmotion of the piston, said battery having a batterylow circuit and saidpiston being programmed to perform the reciprocating motion atdetectable amplitude and frequency as a notification for batteryrecharge or replacement upon receiving a battery low signal from thebattery-low circuit.

55. An implantable drug delivery device of [54] wherein said piston isretracted for a predetermined distance and driven for said reciprocatingmotion without dispensing the drug fluid.

56. An implantable drug delivery device of [54] or [55] having apositive-closing valve attached to said drug fluid chamber, saidpositive-closing valve remaining at closed position when the piston isretracted for said distance and performing said reciprocating motion.

57. An implantable dual drug delivery device comprising:

a. a first drug chamber containing a first drug fluid and having a firstoutlet, a septum and a first piston,

b. a first magnet having a first polarity attached to the septum of saidfirst drug chamber,

c. a second drug chamber containing a second drug fluid and having asecond outlet, a septum and a second piston,

d. a second magnet having a second polarity attached to the septum ofsaid second drug chamber, the second polarity being opposite to thefirst magnet polarity,

58. An implantable dual drug delivery device of [57] including anexternal chamber, said external chamber containing a third fluidenclosed partially by a collapsible soft layer, said third fluid beingseparated from the first drug fluid and the second drug fluid by thefirst piston and the second piston.

59. An implantable dual drug delivery device of [57] wherein said firstand second magnets are ring magnets.

60. An implantable dual drug delivery device of [57] wherein the firstpiston is driven by a first motor and the second piston is driven by asecond motor.

61. An implantable dual drug delivery device comprising:

a. a first drug chamber containing first drug fluid, said first drugfluid chamber being divided by a wall having a one-way valve into afirst compartment having a piston and a second compartment having afollower,

b. a second drug chamber containing second drug fluid, said second drugfluid chamber being divided by a wall having a one-way valve into afirst compartment having a piston and a second compartment having afollower,

c. a first catheter and a first septum being attached to said first drugchamber, said first catheter having opposing walls forming a flowchannel in communication with the first drug compartment, said opposingwalls can be forced to contact each other to block the flow of the firstdrug fluid,

d. a second catheter and a second septum being attached to said seconddrug chamber, said second catheter having opposing walls forming a flowchannel in communication with the second drug compartment, said opposingwalls can be forced to contact each other to block the flow of thesecond drug fluid,

e. a first magnet having a first polarity being attached to the septumof said first drug chamber,

f. a second magnet having a second polarity being attached to the septumof said second drug chamber, the second polarity being opposite to thefirst polarity.

62. An implantable dual drug delivery device of [61] having an externalchamber containing a third fluid, enclosed partially by a collapsiblesoft layer, said third fluid being separated from the first drug fluidand the second drug fluid by the pistons and the followers.

63. A refill container for refilling an implantable dual drug deliverydevice comprising:

a. a tubular housing wall containing a drug fluid, said tubular housinghaving a valve chamber with a top opening end and a reservoir chamberwith a bottom enclosed end,

b. a needle attached to the top opening end of the valve chamber,

c. an orifice plate being positioned separating the valve chamber andthe reservoir chamber, said orifice plate having an orifice at thecenter for passing the drug fluid from the reservoir chamber to thevalve chamber.

d. a magnet valve having a polarity and being movably attached to thevalve chamber, said magnet valve blocks the opening of the orifice platewhen moved in contact with the orifice plate

and allows for the flow from the reservoir chamber to the needle whensaid magnet valve is moved away from the orifice plate.

64. A refill container for refilling an implantable dual drug deliverydevice of [63] wherein said magnet valve having a platform including acentral solid area and slot openings, said central solid area capable ofblocking the orifice of the orifice plate and said slot openings areblocked by said orifice plate when said magnet valve is moved in contactwith the orifice plate.

65. An implantable dual drug delivery device and refill systemcomprising:

a. a first refill container containing a first drug fluid having a ringmagnet valve with a first polarity,

b. a second refill container containing a second drug fluid having aring magnet valve with a second polarity,

c. a first drug chamber containing a first drug fluid and having anoutlet, a septum and a first piston, said septum being attached with afirst magnet with first polarity attracting the ring magnet valve of thefirst refill container,

d. a second drug chamber containing a second drug fluid and having anoutlet, a septum and a second piston, said septum being attached with asecond magnet with second polarity attracting the magnet valve of thesecond refill container, said second polarity being opposite to thefirst polarity of said first refill container.

66. An implantable dual drug delivery device and refill system of [65]wherein the first ring magnet of said first drug chamber repels themagnet valve of the second refill container thereby blocking the drugflow inside the second refill container.

67. An implantable dual drug delivery device and refill system of [57]or [65] wherein the first piston is driven by a first motor and thesecond piston is driven by a second motor.

68. An implantable dual drug delivery device of [67] including anexternal chamber, said external chamber containing a third fluidenclosed partially by a collapsible soft layer, said third fluid beingseparated from the first drug fluid and the second drug fluid by thefirst piston and the second piston.

69. An implantable dual drug delivery device and refill system of [57]or [67] wherein the outlet of each drug chamber is attached with acatheter with a slit valve mounted at the dispensing tip, said slitvalve opens when the piston in each drug chamber moves toward the outletand closes when the piston moves away from the outlet.

70. An implantable dual drug delivery device and refill system of [57]or [67] wherein the drug fluid in each refill container is drawn into amatched drug chamber by moving the piston away from the outlet.

71. An implantable dual drug delivery device and refill system of [69]wherein the outlet of each drug chamber having opposing walls forming aflow channel in communication with the drug fluid in the chamber, saidopposing walls can be forced to contact each other to block the flowinto the catheter when activated by the needle of a refill container.

72. An implantable dual drug delivery device and refill system of [61],[65] or [69] wherein each outlet has a contact switch, said contactswitch having opposing electrode plates with each electrode plate beingattached to said opposing walls of said outlet walls, and said opposingwalls can be forced to contact each other to block the flow into thecatheter and activate the movement of the piston when activated by theneedle of said refill container causing the drug fluid to be drawn fromthe refill container to the drug chamber.

73. An implantable dual drug delivery device of [57], [61] or [67]including a motor driver, a battery and an IC control board with controlsoftware, said motor driver controls the movements of the first and thesecond pistons through the control software of the IC control board andpowered by the battery.

74. An implantable dual drug delivery device of [57], [61] or [67]wherein each motor is a piezoelectric motor comprising a threaded rodand piezoelectric plates with one end forming a threaded-nutconfiguration and, said threaded rod rotates when said piezoelectricplates being in ultrasonic vibration.

75. An implantable dual drug delivery device of [57], [61] or [65]wherein the two drug chambers are oriented in the same direction.

76. An implantable dual drug delivery pump device of [57], [61] or [65]wherein the two drug chambers are oriented in opposite directions.

77. A process of ensuring positive closing of the slit valve of theimplantable dual drug delivery device of [73] wherein said motor driverwith software control moves each piston forward for a first distance fordispensing the drug fluid and then to move the piston backward for asecond distance to ensure the closing of the slit valve, said firstdistance being larger than the second distance by a value correspondingto a specified amount of the drug fluid being dispensed.

78. A process to verify the movement of a follower in a drug chamber ofan implantable dual drug delivery pump device of [61] including afollower magnet being attached to the follower and measuring thedistance between the follower magnet and the septum magnet by a magnetproximity sensor for determining the position of said follower in thedrug chamber.

79. An implantable dual drug delivery device of [61] or [62] whereinsaid first magnet and second magnet are ring magnets

Single-Drug-Chamber Device Configuration

As shown in FIG. 1a an implantable drug delivery pump device 10 of thepresent invention comprises a pump housing having walls 14 including twofluid chambers separated by a piston with the first chamber 18 as areservoir containing first or drug fluid 20, and the second chamber 22containing second or filler fluid 24 which is enclosed partially by acollapsible wall 26. Second fluid 24 is used as a filler fluid which isinert to the drug fluid and body tissues. Piston 28 prevents fluidcommunication between first chamber 18 and second chamber 22. The pistonis driven by a drive means, powered by battery 71, for infusing thefirst fluid through outlet 34 and reducing the volume of the first fluidin the first chamber with the vacated space filled in by the fillerfluid, which is accompanied by the collapsing of the collapsible wall.The fill-in motion of the filler fluid prevents creation of a vacuumthat, if allowed to exist, can negatively impact the movement of thepiston. In this configuration the walls of the first chamber containingthe drug fluid are rigid with internal contact surfaces not hinderingthe movement of the piston. In addition, walls 51 and 56 of the firstand the second chambers 18 and 22, respectively, are impermeable toexternal fluids present in a body tissue environment. In particular,wall 51 of first chamber 18 is made of a drug-compatible, implantablematerial of sufficient rigidity without deformation so as not to hinderthe movement of piston inside the reservoir chamber. For example, thewall material of the first chamber may be constructed from a metal, suchas titanium, nickel titanium, stainless steel, anodized aluminum, ortantalum, or a plastic, such as polyethylene, nylon, or polyurethane.However, wall 56 of second chamber 22 is made of flexible material suchas silicone, polyurethane, which allows the wall to expand or collapseas fluid is added or withdrawn from the first chamber into the secondchamber. A bellow configuration 26 is illustrated in FIG. 1a inrepresenting the collapsible nature of the second chamber to enable themovement of the filler fluid in filling in the space reduced or vacatedby the dispensing of the first fluid. Furthermore, a catheter 48 isattached to outlet 34 of first chamber 18 in flow communication with thefirst fluid 20. The wall of the first chamber includes a filling septum44, which enables a physician to inject drugs into the drug chamber. Anoutlet valve in a form of slit valve 52 is attached at dispensing end ofthe catheter. A normally closed slit valve prevents backflow of fluidsfrom the outside environment into the device. The slit valve is forcedto open by the forward movement 60 of the piston exerting pumpingpressure allowing the drug to be dosed from the reservoir to thetreatment site. The implantable pump device is implanted into a bodycavity, and the catheter can be led to an appropriate tissue or spacefor dispensing the drug.

Piston Motion

The first fluid 20 is pushed by the forward movement 60 of piston 28.The piston performs forward and backward motions under the control of amotor driver, which is mounted in IC control board 32 and ispreprogrammed. The perimeter surface of the piston is in sliding-sealingfit, represented by O-ring 61, with the inner wall surface of the firstchamber. During the forward motion of the piston the slit valve at theend of the catheter is forced to open to dispense the therapeuticliquid. As a result, the second fluid from the second chamber enters thefirst chamber through the flow gaps 64 to fill in the space behind thepiston head left by the movement of the piston. The sliding-sealing fitor the wiping contact of the piston perimeter surface with the innerwall of the first chamber ensures no residual trace of drug fluid, i.e.the first fluid, left behind the piston in contact with the fillerfluid, i.e. the second fluid, and similarly no residual trace of thefiller fluid left on the opposite side of the piston will be in contactwith the drug fluid.

The filling motion of the filler fluid into the first chamber reducesthe volume in the second chamber, therefore, causes the bellow wall orthe collapsible wall to close in. Conversely, a backward or retractingmotion of the piston creates a negative pressure drop that causes theslit valve to close. With the slit valve closed, further retraction ofthe piston is hindered due to vacuum pressure created inside the firstchamber. For a given drug dosage at each infusion event, the number offorward pulses and the immediate number of backward pulses can bepredetermined for the device to provide the desired net amount of drugdispensed at the event through the slit valve. In each infusion eventthe number of forward pulses or forward distance is greater than thenumber of backward pulses or backward distance which results in thedesirable amount of drug dosage exiting from the one-way slit valve atthe dispensing end of the catheter. Moreover, the capability of thereciprocating motion of the piston can be utilized for refillingnotification as will be described in later sections.

Slit Valve

In a preferred embodiment a positive-closing slit valve 52 is a moldeddome-shaped cap of elastomeric materials having a cross-slit cut forminga plurality of flexible flappers. In a preferred embodiment a slit valveused for the implantable drug delivery pump device of this invention isof a biocompatible silicone material. The slit valve has a tubular wallbase and four flappers. Each flapper is a curved triangular valvesegment extending from the tubular wall base with the tip of each valvesegment intercepting at the center, i.e. at the apex of the slit valveopening when the slit valve is at the closed position. Each valvesegment can be bent like a cantilever beam under the pressure of adispensing flow. The slit length, wall thickness and the elastic modulusof the valve material are designed to ensure self-closing of the slitvalve by the resiliency and the vacuum force at the absence of pumpingpressure. With the use of a slit-valve, it is not necessary to use anoutlet check valve to prevent backflow.

The valve opens under positive piston pressure to dispense first fluidand the cross-slit valve closes under negative piston pressure when thepiston is moved away from the outlet by the drive means. In practice,infusion of the drug is achieved in pulsed steps at predetermined timeintervals. In each repeated infusion events, the therapeutic fluid isincrementally dispensed and the collapsible wall or the bellow wall ismoving forward in each cycle. This process continues until the firstchamber 18, i.e. the drug reservoir, is depleted of the first or thedrug fluid. As shown in FIG. 1b , in the drug-spent or reservoir emptystate the space 72 behind the piston in first chamber 18 is full of thefiller fluid 24. A dispensing phase starts from the piston home position62, which is defined as the piston top surface 63 in contact with thefirst fluid being at the lower travel limit of the piston, and ends whenthe piston's top surface is at the upper travel limit 66.

Refilling

Referring to FIGS. 2a and 2b , refilling of the drug chamber can beaccomplished by inserting a needle 80 of a refill container 84 into aseptum 88 of the drug delivery pump device 10. In one embodiment refillcontainer 84 having drug fluid 71 comprises a tubular housing wall 89having a first opening 86 and second opening 91, disc 87, magnet 96 andneedle 80. Disc 87 is in movable fit with the inner wall of housing 89and the opening 89 maintains the disc at ambient pressure. To preventexternal actuation, disc 87 is not accessible manually from outsidehousing 89 and it is only movable when following the flow directiontoward the needle when the drug fluid is drawing out of the housingthrough the needle. Magnet 96 is preferably a ring magnet. Both magnet96 and needle 80 are attached to housing wall 89 with the needle beingattached to second opening 91 for the passage of drug fluid 71. FIG. 2ashows refill container 84 being full of refill drug fluid 71. Magnet 96surrounds the needle to guide the positioning of the needle wheninserting to septum 88 which is attached with magnet 92. In anotherembodiment, the refill container for an implantable drug delivery deviceof this present invention uses a collapsible pouch having a thinflexible wall for containing a drug fluid. No movable disc is required.FIG. 2c shows a refill container assembly 184 using a rigid outerhousing wall 189 to shield the collapsible pouch 188. The thin flexiblewall 187 of collapsible pouch 188 is fastened to a top plate 190 formingan enclosure containing drug fluid 171. The top plate has exit opening191 as a flow path for the drug fluid drawn out of the collapsiblepouch. Needle 180 is attached to the exit opening 191 by threadedengagement between the needle and the housing. Alternatively, the needlemay be directly threaded onto the top plate 190 of the pouch. FIGS. 2cand 2d illustrate the assembly housing comprising two foldable halves150 and 152 for ease of inserting the collapsible pouch and mounting theneedle. With this foldable configuration magnet ring 196, whichsurrounds the needle, may be divided into two halves with each attachedto a half of the housing wall. To prevent external ambient pressure fromcontracting the collapsible pouch and forcing out the drug fluid, theexternal housing wall 189 is designed to be rigid and not deformable tocontact on the collapsible pouch. Optionally, gap 154 exits between thehousing wall 189, which is of tubular form, and the collapsible pouch188 such that the housing wall does not deform preventing contraction ofthe collapsible pouch which would have resulted in inadvertentdispensing of the drug fluid. FIG. 2d shows that collapsible pouch 188contracts only when drug fluid 171 is drawn out from needle 180 under avacuum 195, which occurs during the refilling process when the needle isinserted into the septum of drug delivery device 10. This passive typeof refill container which depends on insertion into the septum of a drugdelivery device for withdrawing the drug fluid is a safety feature toprevent inadvertent injection of the drug fluid into body tissues if thedevice is not properly connected to the septum.

For the insertion of a refill container needle, magnet 92 attached toseptum 88 is preferably a raised ring for guiding the positioning of theneedle through the skin 98. The raised ring 92 may be in a form of ringmagnet of a polarity that attracts a ring magnet 96 of opposite polaritymounted on the needle 80 of the refill container 84. The attractionbetween the two magnets 92 and 96 across the skin can facilitatepositioning and stabilizing the needle 80 during injection. PDMS, whichis Polydimethylsiloxane a silicon-based organic polymer material, may beselected as a septum material for its flexibility and ability to resealitself after repeated punctures via a needle attached to the refillcontainer.

As a reverse of the dispensing function, the retraction or backwardmovement of the piston draws the refill fluid from the refill containerinto the first chamber. Continuous retracting motion of the piston candraw in the refill fluid to fill the first chamber while the catheterentrance remains closed by the negative pressure drop. FIG. 2 showscompletion of a refilling process and the piston is at its home position62. The refill container is of the “passive type” and does not have aplunger thereby minimizing the risk of inadvertently injecting drug intoa body cavity. Refilling from the refill container is possible only whenthe needle is inserted into the septum and the retracting action of thepiston draws in the drug solution by vacuum, a safety feature of thisinvention as described. As the piston is retracted the collapsible wall56 expands corresponding to the volume of the refill-fluid being drawninto the first chamber.

Activation Detector

To ensure a readiness for refilling, the refilling process can startonly when an activation detector is activated. The permanent magnet 92mounted on septum 88 as shown in FIG. 2 is attached with an internalmagnet proximity sensor (not shown) to function as an activationdetector for triggering the controller and the motor driver in controlboard 32. The use of a magnet proximity sensor using Hall Effect fortuning the operational gradient of the magnetic field normal to the faceof the detector is known in the art. Commercially magneto-resistivesensors of the Honeywell Company may be used as an activation detector.These sensors have a high sensitivity with conventional magnets likeAlNiCo and ceramic materials and their Wheatstone bridge elementsconvert the magnetic field direction into a voltage output. Optionally,a Reed Sensor of Cherry Corporation may be used as a magneticallyactivated switch. The internal magnet proximity sensor (not shown) is inelectrical communication with the motor driver and the microprocessor inthe IC board of the pump device. To save space in the septum area theHall Effect circuit 35 of the magnet proximity sensor is integrated inthe IC board 32. When a specified starter-magnet, for activating thepump device, is placed on top of the magnet ring 92 of the pump device10 across the skin 98, the activation detector (not shown) detects thechange of the magnetic field surrounding the magnet ring 92 and thecircuit of the proximity sensor converts the change of magnetic fieldinto a voltage output. The activation detector triggers the controllerand the motor driver to start the dispensing function of the pump devicewith forward motion of the piston. Similarly, when starting a refillingprocess, a specified refill-magnet is placed on top of the magnet ring92 across the skin. The refill-magnet is preferably being magnet 96attached to the needle or part of the refill container. Thus theapproaching and docking of a refill container needle can cause theactivation detector to activate the pump device with backward motion ofthe piston for refilling the drug chamber.

Notification Mode

For a given implantable drug delivery device and a given infusionprofile for a patient, the refill interval is known and, therefore, thetime to refill can be planned. However, if refilling does not occur atthe appropriate time, a notification signal can be sent by theimplantable drug delivery device of this invention. The notificationfeature utilizes the reciprocating motion of the piston. The motordriver can be programmed to perform a reciprocating motion of the pistonat the end of a dispensing cycle to signal for refilling. The amplitudeand the frequency of the reciprocating motion are pre-tested forgenerating a vibration of the pump device which does not cause any harmbut is detectable by the patient. As a reminder to the patient to havethe device refilled the reciprocating motion may be repeated to signalat a prescribed interval, which is to be determined (TBD) for a patientusing the device. For instance the notification mode or the oscillationof the piston may be programmed to repeat at every 12 or 24 hours,depending on the drug and other factors such as coinciding withconvenient day time schedules for taking action.

Verification

Additionally, there are a number of factors that may cause performancefailures of an implanted device. These factors include the malfunctionof electronics, hesitation in piston movement, voids in the drugreservoir and possible clogging at the dispensing opening. Therefore, anindependent verification of the performance of an implant device isessential to ensure the reliable and predictable performance for thedevice. For verification of the pump performance of the presentinvention the position of the piston or a residual amount of dispensingmaterial in the first chamber can be measured externally. As shown inFIG. 2, piston 28 is fitted with a magnet 76 and the displacement of themagnet mounted on top of the piston can be determined by measuring thedistance 70 between the piston magnet 76 and the septum magnet 92, whichis positioned at the center of the septum. The distance between the twomagnets can be measured by an external magnetic proximity sensorpositioned across the skin. A magnetic proximity sensor can be acommercially available Honeywell HMC1501 or HMC1512 magneto-resistivesensor. These sensors feature Wheatstone bridge elements to convert themagnetic field into a voltage output. The HMC sensors provide reliableperformance in accuracy and resolution. This pump performanceverification method is more convenient than a method of softwareinterrogation of the number of pulses recorded in the microprocessorchip used for controlling the piston motion for dispensing drug dosages.

Piezoelectric Motor

A drive means of an implantable drug delivery pump device of the presentinvention can be a threaded rod 81 driven by motor 36 as illustrated inFIG. 1a . The rotation of the threaded rod 81 causes forward andbackward movements of piston 28 corresponding to the rotationaldirection of the motor. As noted previously the mounting of motor 36creates flow gaps 64 to allow second fluid 24 enter the first chamberbehind the piston separating from the first fluid 20. The second fluidis partially enclosed by the collapsible wall represented by the bellow26.

Preferably, a motor is a piezoelectric motor 36 as illustrated in FIG.1a comprising a threaded rod and piezoelectric plates with one endforming a threaded-nut configuration (not shown). The vibration of thepiezoelectric plates can cause the threaded rod to rotate. The threadedrod 56 is in free-to-rotate engagement with the piston 28. Generally thepiston may have a non-circular cross-section undergoing linear movementwithout rotation. The conversion of the rotational motion of threadedrod 81 to a linear motion of the piston is achieved by using arotational sleeve 83 and rotational retainer 85. The assembly contains ameans for subjecting the threaded nut to ultrasonic vibration causingthe threaded shaft to simultaneously rotate and translate in the axialdirection. A cylinder supports a threaded nut with a first bending moderesonant frequency in the ultrasonic range. The cylinder and nut areexcited at this resonant frequency by transducers that cause the nut toorbit at the end of the cylinder. The transducers may be piezoelectric,electromagnetic or any device that can stimulate the resonant vibration.A detailed description of a piezoelectric motor is given in U.S. Pat.No. 6,940,209 by Henderson.

Stepper Motor

Alternatively as shown in FIG. 3, a piston in an implantable drugdelivery pump device of the present invention can be driven by a steppermotor which comprises coils 350 and a threaded shaft 356. Fordescription purposes, FIG. 3 shows an implantable drug delivery pumpdevice 310 of the present invention comprising a pump housing havingwalls 314 including two fluid chambers separated by piston 328 with thefirst chamber 318 as a reservoir containing first or drug fluid 320, andthe second chamber 322 containing second or filler fluid 324 which isenclosed partially by a collapsible wall 326. Flow gaps behind thepiston head allow the second fluid to enter the first chamber preventingany vacuum as the piston moves. Piston 328 is driven by stepper motor370, which is mounted with thread shaft 356.

Generally piston 328 has a non-circular cross-section and is attachedwith a free-to-rotate sleeve 383 and rotational retainer 385 to convertthe rotational motion of the thread shaft to a linear motion of thepiston. The displacement of the piston is proportional to the number ofpulses given to the motor coils. The use of a stepper motor isparticularly advantageous because the signals applied to its coils aredirectly related to the displacement of the piston without requiringshaft encoders or sensors. The stepper motor is controlled by thecontrol board 332 which includes an oscillator and a microprocessor andpowered by battery 371. Optionally the oscillator may also be incommunication with an external controller by passive telemetry formonitoring and correction of the performance of the device.

Induction Coils

Another alternative for driving a piston involves using induction coils.A piston made of electromagnetic or ferrite material can be magnetizedby induction coils when an electric current passes through the coil. Fordescription purpose, FIG. 4a shows an implantable drug delivery pumpdevice 410 of the present invention that comprises a pump housing havingwalls 414 including two fluid chambers separated by piston 428 with thefirst chamber 418 as a reservoir containing first or drug fluid 420, andthe second chamber 422 containing second or filler fluid 424 which isenclosed partially by a collapsible wall 426. Flow opening 464 allowssecond fluid 424 to enter first chamber behind piston 428 separatingfrom the first fluid. Piston 428 is driven by electrical coils 430mounted in the annular gap of a cylindrical housing 414 and in asliding-and-sealing fit with the inner surface of the housing wall 444.A drive means for a piston of an implantable drug delivery pump deviceof the present invention comprises a permanent magnet 458 positioned atthe outlet end 434 of the first chamber 418 and induction coils 430being supported by the housing wall 444. The induction coils magnetizethe piston to move in forward and backward directions depending on thepolarity of the magnetic field induced by the induction coils inresponding to the direction of the electrical current imposed on theinduction coils. Piston 428 moves toward the outlet position 434 whenthe piston is magnetized with a polarity in the same polarity directionas the permanent magnet 458, and the piston moves away from the outletposition when the piston is magnetized with a polarity in the oppositepolarity direction to that of the permanent magnet. For an implantabledrug delivery pump device 410 of the present invention using inductioncoils for driving a piston, the dispensing cycle, the refilling processis similar to what has been described previously. Infusion pump 410 mayalso include the aforementioned activation detector and verificationfeatures. Furthermore, the control of the pump device 410 isaccomplished by an external device containing induction coils 460, whichis positioned across the skin 408 opposite to the induction coils 430 ofthe pump device. FIG. 4b shows a pump device 410 at the empty state withpiston 428 reaching the maximum of travel distance near the outletopening 434 and the wall of bellow 426 collapsing due to the flow ofsecond fluid 424 filling in the space behind the piston. Also shown inFIG. 4b is needle 409 of the refilling syringe 470 inserted in septum406 to start a refilling process, which is controlled by an externalcontroller (not shown) represented by induction coils 460.

The timing and frequency of the current pulses applied to the coils canbe controlled by an external controller (not shown). Use of an externalcontroller for changing the operational parameter set is well known inthe art, such as described in US Patent Application 20080108862 byJordan; Alain et al. All the activity of the pump is recorded in amemory and a patient can access the data and change the pump parametersby radio frequency (RF) communication with an external control unit. Analternative method without using an RF emitter in an implanted device as“passive telemetry by absorption modulation” by P. A. Neukomm isdescribed in CH 676164, WO 89111701, EP 0377695 and in the articlePassive Wireless Actuator Control and Sensor Signal Transmission,Sensors and Actuators, A21-A23 (1990), 258-262.

Software Control Elements

The control software in the microprocessor controller of the presentinvention is programmed to provide Dispensing Mode, Refilling Mode,Notification Mode and Verification-Calibration Mode. In the DispensingMode, the microprocessor commands to provide pulses of differentdurations to control the dispensing rates depending on a prescribeddosage profile, which are converted into a set of operational parametersfor the operation of the motor driver. At each dispensing command, afterthe pre-determined forward pulses, a pre-determined number of backwardpulses follow to ensure positive-closing of the slit valve. The requirednumber of backward pulses for closing the slit valve is less than thenumber of forward pulsed for dispensing such that the desirable amountof drug dosage is dispensed. The schedules and timings of the controlleraction are based on inputs from an IC oscillator timer built in the ICboard of the pump device. The IC circuit for an oscillator timer is wellknown in the art. With an external controller, the operational parameterset (OPS) in the implant pump of the present invention can be changed asneeded. In addition a memory chip in the pump device records the historyof forward and backward pulses. An algorithm is provided in the controlprogram to monitor the current amount of drug remaining in the reservoirsuch that the timing for refilling the reservoir is determined. Themaximum travel distance of the piston between the reservoir full andreservoir empty is converted into the maximum number of dispensingpulses, which is pre-programmed with a safety factor in the controller.When the maximum number of dispensing pulses is reached, no furtherforward movement of the piston is commanded.

In the Refilling Mode, the needle of a refill container is inserted intothe septum and the content is drawn into the first chamber by theretraction of the pump piston. The refill container is of a passive typewithout having an active plunger for external manual injection,therefore, preventing accidental administration of drug into wrong bodytissues. The docking of the needle with the approach of therefill-magnet on the refill container initiates the refilling mode, andthe controller microprocessor of the pump device of the presentinvention commands the motor driver to start the retraction motion ofthe piston. The motor may be programmed to run at a higher retractionspeed at the refilling mode than the speed at the dispensing mode. Theduration of the refilling mode is pre-programmed according to themaximum traveling distance of the piston for complete filling of thereservoir.

The Notification Mode can be programmed for repeated vibration of thepump device to alert the patient to take action to have the pump devicerefilled. The piston oscillation is initiated at the end of theDispensing Mode, therefore, no additional drug is dispensed from theslit valve at the Notification Mode. The reciprocation of the piston isoperated at detectable amplitude and frequency for a short duration suchas a few seconds. The objective is to create vibrations which do notcause any harm or discomfort to the patient but are adequate to alertthe patient to take action. At the Notification Mode, the command forthe oscillation motion of the piston is repeated over a time interval.

In the Verification-Calibration Mode, the control program of theinfusion pump of the present invention uses the input of a magneticproximity sensor to measure the distance between the two magnets in theimplant pump. The measured distance between the two magnets is convertedand compared to the number of pulses for dispensing as recorded in thememory chip. Any discrepancy will be re-adjusted and re-calibrated inthe operational parameter set to achieve a correct dispensing profilefor continuous usage of the pump device. Such a verification-calibrationmode may be integrated with the refilling mode such that theverification-calibration mode is conducted prior to the refillingaction.

As a summary, FIG. 5 shows the interactions of the operation modes ofthe software control program of the implantable drug delivery pumpdevice of the present invention.

In summary, the implantable drug delivery pump device of the presentinvention provides a drug reservoir chamber having a piston and a fillerchamber having a collapsible wall to facilitate the dispensing motion ofthe piston. With a slit valve attached to the catheter dispensing end,the software controlled retraction motion of the piston enables positiveclosing of the dispensing valve to prevent clogging and for refilling ofthe drug reservoir. The Notification Mode activates detectableoscillation of the piston to alert the user to take refilling actions.The verification and calibration feature uses external measurement ofthe distance between two magnets in the pump device to ensure reliableperformance of the pump device of the present invention.

Although the invention has been described with reference to particularembodiments, the description is only an example of the invention'sapplication and should not be taken as a limitation. Various otheradaptations and combinations of features of the embodiments disclosedare within the scope of the invention as defined by the followingclaims.

Divided-Drug-Chamber Device Configuration

The infusion pump of this invention comprises a divided first chambercontaining a first fluid and a second chamber, enclosed partially bycollapsible walls, that contains a second fluid. FIGS. 6a, 6b and 6cshow an infusion pump 10A of the present invention including housingwalls 14A that encompass first chamber 18A containing first fluid 20Aand second chamber 22A containing second fluid 24A. The first chamber18A is a drug reservoir containing first fluid 20A and it is dividedinto a first compartment 11A and a second compartment 13A by a wall 15Amounted with a one-way valve 17A. FIG. 6b shows a top cross-section viewof the division between the two compartments 11A and 13A by the wall 15Aand the one-way valve 17A. FIG. 6c shows the extension of the dividingwall 15A and the one-way valve 17A into septum 44A of the implant device10A. The one-way valve provides a flow path 23A as shown in FIG. 7a andFIG. 7b between the first and the second compartments 11A and 13A whenthe valve 17A is in the open position. The first compartment 11A has apiston 83A connected to a driving means and the second compartment 13Ahas a follower 28A, which is in flow communication with the movement ofthe piston 83A The wall of the second chamber 22A is collapsible asrepresented by a bellows wall 56A as shown in FIG. 6a . The second fluid24A, which is inert to the drug fluid and body tissues, serves as afiller fluid in communication with the first fluid chamber to fill thespace evacuated by the movements of the piston and the follower toprevent creation of a partial vacuum that could negatively impact themovement of the piston and the follower. Both piston 83A and follower28A separate second fluid 24A from first fluid 20A. The piston is drivenby a drive means for infusing the first fluid through outlet 34A andreducing the volume of the first fluid in the first compartment. In thisdivided drug chamber configuration, the drug dosage dispensed at eachstep of the piston forward movement is a small fraction of the amountfor an un-divided configuration.

Furthermore, a catheter 48A is attached to outlet 34A of first chamber18A in communication with the first fluid 20A. The wall 51A of the firstchamber includes a filling septum 44A for inserting needle 85A of arefill container to inject a refill drug into the drug chamber. Anoutlet valve in a form of a slit-valve 52A is attached at the dispensingend of the catheter. A normally-closed slit-valve prevents backflow offluids from the external environment into the device. The slit-valve isforced open by the forward movement of the piston exerting pumpingpressure allowing the drug to be dosed from the reservoir to thetreatment site. The implantable device is implanted into a patient'sbody, and the catheter can be led to a treatment location where the drugis dispensed. Depending on the geometry and the stiffness of theslit-valve elements, the slit-valve may be partially or fully opencorresponding to the steps of the piston advancement. Following a stepof dispensing drug, if further piston advancement is minute theslit-valve may be partially open without further dispensing the drugfluid out of the catheter. Being immersed with the dispensed drug stillat the valve exit, the drug inside the valve opening is not mixed withthe body fluid, which has been pushed away from the valve opening.

Reciprocating Piston Motion

The piston performs a reciprocating motion under the control of a motordriver that is mounted in an IC control board 32A as shown in FIG. 6A,and is preprogrammed. The first fluid is pushed by the forward movementof the piston. The perimeter surface of the piston is in sliding-sealingfit, represented by O-ring 61A, with the inner wall surface of the firstcompartment. The sliding-sealing fit or the wiping contact of the pistonperimeter surface with the inner wall of the first compartment ensuresno residual trace of drug fluid, i.e. the first fluid, comes in contactwith the filler fluid on the opposite side of the piston. During theforward motion of the piston the one-way valve is forced to close andthe slit-valve at the end of the catheter is forced to open to dispensethe first fluid. During the backward motion of the piston a partialvacuum is created in the first compartment that causes the slit-valve toclose and the one-way valve to open. As a result, the first fluid 20Afrom the second compartment 13A enters the first compartment IIA throughthe valve opening 25A (shown in FIG. 7a ). Simultaneously, the follower28A in the second compartment 13A moves forward, which induces thefiller fluid 24 to fill the space left by the movement of the followerthrough the flow gaps 64A to fill the space left by the movement of thepiston. The sliding-sealing fit or the wiping contact of the followerperimeter surface with the inner wall of the second compartment ensuresno residual trace of drug fluid comes in contact with the filler fluid.

The filling motion of the filler fluid into the first and the secondchambers reduces the volume in the second chamber, thereby, causing thebellows or the collapsible wall 56A to contract. With the slit-valveclosed further retraction of the piston is hindered due to the partialvacuum created inside the first compartment. For a given drug dosage ateach infusion event, the number of forward pulses and the immediatenumber of backward pulses can be predetermined for the device to providethe desired net amount of drug dispensed at the event through theslit-valve. In subsequent repeated reciprocating motion of the piston,the first fluid is incrementally dispensed and the follower is movingforward in each cycle. This process continues until the secondcompartment is empty. In the empty state, the space behind the followeris full of the filler fluid.

The dispensing process can start only when an activation detector isactivated. The permanent magnet 92A mounted on septum 44A as shown inFIG. 6c is attached with an internal magnet proximity sensor (not shown)to function as an activation detector for triggering the controller andthe motor driver in control board 32A. The use of a magnet proximitysensor using Hall Effect for tuning the operational gradient of themagnetic field normal to the face of the detector is known in the art.Commercially magneto-resistive sensors of the Honeywell Company may beused as an activation detector. These sensors have a high sensitivitywith conventional magnets like AlNiCo and ceramic materials and theirWheatstone bridge elements convert the magnetic field direction into avoltage output. Optionally, a Reed Sensor of Cherry Corporation may beused as a magnetically activated switch. The internal magnet proximitysensor (not shown) is in electrical communication with the motor driverand the microprocessor in the IC board of the pump device. To save spacein the septum area the Hall Effect circuit of the magnet proximitysensor is integrated in the IC board 32A. When a specifiedstarter-magnet, for activating the pump device, is placed on top of themagnet ring 92A of the pump device 10A across the skin (not shown), theactivation detector (not shown) detects the change of the magnetic fieldsurrounding the magnet ring 92A and the circuit of the proximity sensorconverts the change of magnetic field into a voltage output. Theactivation detector triggers the controller and the motor driver tostart the dispensing function of the pump device.

Priming Steps

To avoid dead spaces, voids or air pockets in a drug delivery device ofthe present invention, the priming steps for complete filling of thedevice with drug fluid and filler fluid are as follows.

Referring to a preferred embodiment as shown in FIGS. 9a, 9b and FIGS.10a, 10b, 10c, 10d and to start with a new and empty condition andbefore implanting the device, 1) squeeze and keep the slit valve at opencondition, then move follower 128A to the lower travel limit, i.e. thebottom home position, 2) move piston 183A to the upper travel limitposition, 3) insert an active plunger syringe pre-filled with the drugfluid to the tip of needle into septum 144A without opening one-wayvalve 117A (shown in FIG. 10c ), 4) inject the drug fluid to fill upsecond compartment 113A completely with any possible air bubbles rising(not shown) against the gravity direction in the septum cavity, 5) withthe slit valve remaining open, push the syringe needle further to openthe one-way valve, 6) inject drug fluid to fill up the septum and thecatheter and expel the air through the slit valve 52A, 7) release theslit valve to resume its self-closing position and retract the pistonall the way to the lower travel limit to draw the drug fluid to fill thefirst compartment completely, 8) remove the syringe from the septum, 9)insert an active-plunger filler fluid syringe needle into the injectionport of the filler fluid chamber at the gap under the follower, 10)insert vent needles (not shown) through the wall of the filler fluidchamber at extreme locations of the injection flow path of the fillerfluid from the filler fluid injection port for venting air, 11) injectthe filler fluid to fill up the filler fluid chamber completely andexpel the air through the vent needles, 12) remove the filler fluidsyringe and the vent needles. Alternatively, the evacuation of the aircan be facilitated by a vacuum means attached to the vent needle duringthe injection of the filler fluid into the chamber. In addition, thewall areas for inserting the vent needle and the filler fluid syringeneedle are of resilient material, which is penetrable and self-closingwhen the needles are removed. After the above priming steps the deviceis completely filled with the drug fluid in the first and secondcompartments of the drug chamber and with the filler fluid in the fillerfluid chamber without any dead spaces, voids or air pockets in thedevice.

Refilling Process

Refilling of the first chamber can be accomplished by inserting a refillcontainer 84A into the septum 44A of the pump device 10A as shown inFIGS. 8c and 8d . The septum has a raised ring (not shown) to facilitatethe positioning of the needle through the skin. FIGS. 8a, 8b, 8c and 8dillustrate a sequence of refilling steps. FIG. 8a shows an implantabledrug delivery pump device 10A of FIG. 6c at full state with both thepiston 83A and the follower 28A at their home positions. The homeposition of the follower is the lower travel limit of the follower. Aforward movement 60A of the piston 83A toward the slit-valve 52A causesthe slit-valve to open under the pumping pressure as shown in FIG. 8b .After repeated forward and backward movements of the piston the firstchamber becomes empty as shown in FIG. 8b where the follower 28A reachesthe top 35A of the second compartment 13A. The top of the secondcompartment is the upper travel limit of the follower. To refill thedevice, a refill container 84A containing refill drug 37 A is insertedinto the septum 44A of the device 10A as shown in FIG. 8c . Referring toenlarged views of the flap-type one-way valve mechanism 17A as shown inFIGS. 7a and 7b , correct positioning of the refill container enablesthe needle 85A to push open the one-way valve 17A toward the catheterwall 48A. Further pushing of the needle 85A causes the catheter wall 48Ato block the flow of the first fluid 20A into the catheter 48A. Forcingthe catheter walls 48A to touch also enables the contact of two thinelectrode elements 81A forming a contact switch, which is in electricalcommunication with the motor driver in the IC control board 32A, toactivate the reciprocating or pumping motion of the piston. As a reverseof the dispensing function, retraction or backward movement of thepiston draws the refill fluid 37A from the refill container 84A into thefirst compartment 11A and a subsequent forward movement pushes therefill fluid from the first compartment 11A into the second compartment13A through the valve opening 25A. A series of reciprocating motion ofthe piston draws in the refill fluid from the refill container anddelivers it into the second chamber until both the first and the secondchambers are full of the refill fluid. Simultaneously during therefilling process the filler fluid 24 is returned to the bellows throughthe flow gap 64A, which is in communication with the filler fluid behindthe piston and the follower and the filler fluid in the bellows. Duringthese fluid movements the catheter entrance remains closed by thecontact of the refill container needle against the catheter walls. Therefill container is preferably a passive type not using anexternally-actuated plunger, which is a safety feature for avoiding anyaccidental injection. As shown in FIG. 8c , refill container 84A usesinternal disc 87A, which is in sliding fit with the inner wall of thecontainer, for compacting drug fluid 37A. FIG. 8c shows refill container84A being full of refill drug fluid 37A in the beginning of therefilling process. After completion of the refill process the refillcontainer is depleted of the drug fluid and pulled from the septum asshown in FIG. 8d . At the completion of a refilling process and when thefirst chamber is full, the piston and the follower are at their homepositions and the bellows is at its fully expanded shape.

Instead of using the flap-type valve 17A as shown in FIG. 7a , aplunger-type valve in a divided drug chamber of an implantable drugdelivery device 1OA′ as shown in FIGS. 7c, 7d can be used for closingthe flow path in the catheter channel by the insertion of the needle ofa refill container. Correct positioning of the refill container enablesthe needle 85A′ to push open the plunger 19A toward the catheter wall48A′. The plunger 19A is attached with an electrode-plate 82A and loadedwith springs 17A′. Further pushing of the needle 85A′ causes theelectrode-plate 82A to block the flow of the first fluid 20A into thecatheter 48A′. Forcing the movable electrode-plate 82A to touchstationary electrode 81A′ also enables forming a contact switch, whichis in electrical communication with the motor driver in the IC controlboard 32A, to activate the reciprocating or pumping motion of piston83A. The slidable electrode plate 82A is a thin plate to minimize thedisplacement of the drug fluid in the catheter and the displaced volumemay enter the septum area through the clearance between the electrodeplate 82A and the catheter wall 48A′. This feature prevents the drugfluid being forced through the catheter valve 52A (shown in FIG. 6A) bythe insertion of the needle. Upon release of the needle, the springsforce the plunger against the partition wall 25A′, which divides pistonchamber 11A and reservoir chamber 13A in the septum area and has opening26 for the insertion of the needle. With the use of the contact switch,a conventional active plunger-type syringe may be used for refilling aspushing of the plunger may assist pushing the drug into the drug chamberin addition to the vacuum force created by the withdrawing of the pistonin the refilling process triggered by the contact switch.

Flexible-Layer Filler-Fluid

Instead of a bellows configuration positioned at the bottom end of adevice such as the bellows 56A shown in FIG. 6a , the collapsible wallof the second chamber containing the second fluid may be a flexible andsoft layer 156A attached to the housing walls 114A forming an externalfluid chamber of the device 100A as shown in FIGS. 9a, 9b and 9c . FIG.9b shows the flexible layer of the second chamber 122A attachedexternally to the housing walls 114A of the implantable device 100A ofthe present invention. Preferably the flexible layer is wrapped from thefront side 116A, around the bottom side 118A, to the back side 119A ofthe housing walls 114A as illustrated in FIG. 9b . Side walls 132A and134A and top wall 136A which is mounted with the septum 144A and thecatheter 148A are not attached with a soft layer for ease ofmanufacturing and manual handling prior to implantation procedures. Withrespect to the flexible external fluid chamber, the first fluid chamberis referred as the internal fluid chamber. In comparison with thebellows configuration as shown in FIG. 6a the flexible-layerconfiguration has the advantage of shorter device length and moreconformable contact with body tissues. FIGS. 9b and 9c also show thefiller-fluid openings 170A and 172A. The first filler-fluid opening 170Aon the first compartment wall 180A is for the entrance and exit of thesecond fluid 124A behind the piston 183A as the piston moves forward andbackward, respectively. On the other hand, the second filler-fluidopening 172A on the second compartment wall 182A is for the entrance andexit of the second fluid behind the follower 128A as the follower movesforward and backward, respectively, following the piston movement.

Openings for the Passage of Filler Fluid

Specifically, FIGS. 10a, 10b, 10c, and 10d show the contraction andexpansion of the external soft layer 156A containing the filler fluid124A in a sequence of the refilling process of device 100A. FIG. 10ashows an implantable drug delivery device 100A of FIG. 9b at the fullstate with both the piston and the follower at their home positions. Aforward movement as indicated by the arrow 160A of the piston 183Atoward the slit-valve 52A causes the slit-valve to open under thepumping pressure. After repeated forward and backward movements of thepiston the second compartment 113A is depleted of first fluid 120A andthe space behind the follower 128A is filled with second fluid 124A asshown in FIG. 10b . For refilling, a needle 185A of refill container184A containing refill drug 137A is inserted into the septum 144A of thedevice 100A as shown in FIG. 10c . Correct positioning of the refillcontainer enables the needle to push the one-way valve 117 A toward thecatheter wall. Further pushing of the needle 185A causes the catheterwalls 149A to block the flow of the first fluid into the catheter. Thetouching of the catheter walls also enables the contact of two thinelectrode elements 181A, which are in electrical communication with themotor driver in IC control board 132A, to activate the reciprocatingmotion of the piston 183A. During retraction or backward movement 162Aof the piston, as shown in FIG. 10c , the drug fluid inside the refillcontainer is drawn into the first compartment while the refill druginside the second compartment is held back by a partial vacuum as thedevice is enclosed by body tissues. The refill container is atatmospheric pressure because of the presence of a vent hole (not shown),The next forward movement of the piston pushes the first fluid into thesecond compartment, similar to flow path 23A indicated in FIG. 7a ,through the edges of the one-way valve opening, which is similar tovalve opening 25A indicated in FIG. 7b . A series of such reciprocatingpumping motions can draw the filler fluid from the soft-layer secondchamber through the first and second filler-fluid openings to fill thespace behind the piston and the follower. At the completion of arefilling process as shown in FIG. 10d , the refill container 184A isempty, the piston and the follower are at their home positions and thesoft-layer chamber is at its fully expanded shape.

Materials of Device Components

Referring to FIG. 6a , walls 54A of the first chamber and collapsiblewalls 56A of the second chamber are impermeable to external fluidspresent in a body tissue environment. In particular, wall 54A of firstchamber 18A is made of a drug-compatible, implantable material ofsufficient rigidity without deformation so as not to hinder the movementof the piston inside the reservoir chamber. For example, the wallmaterial of the first chamber may be constructed from a metal, such astitanium, nickel titanium, stainless steel, anodized aluminum, ortantalum, or a plastic, such as polyethylene, nylon. However,collapsible wall 56A of second chamber 22A is made of flexible materialsuch as silicone or polyurethane, which allows the wall to expand orcollapse as fluid goes in and out of the second chamber. Forself-sealing the septum is made of resilient material. Referring toFIGS. 7a and 7b septum 44A has a raised ring ridge for positioning therefill through the skin. The raised ring ridge may be in the form ofring magnet 92A of a polarity that attracts a ring magnet (not shown) ofopposite polarity mounted on the needle 85A of the refill container 84A.The attraction between the two ring magnets having opposite polaritiesacross the skin can facilitate positioning and stabilizing the refillcontainer needle during the refilling process. The device is implantedpreferably near the treatment site and the slit-valve is to be locatedat the treatment site. In a preferred embodiment the positive-closingslit-valve 52A is a molded dome-shaped cap of elastomeric materialshaving a cross-slit cut forming a plurality of flexible flappers. In apreferred embodiment a slit-valve used for the implantable drug deliverypump of this invention is of biocompatible silicone material. Theslit-valve has a tubular wall base and four flappers. Each flapper is acurved triangular valve segment extending from the tubular wall basewith the tip of each valve segment intercepting at the center, i.e. atthe apex of the slit-valve opening when the slit-valve is at the closedposition. Each valve segment can be bent like a cantilever beam underthe pressure of a dispensing flow. The slit length, wall thickness andthe elastic modulus of the valve material are designed to ensureself-closing of the slit-valve by the resiliency and the vacuum force inthe absence of pumping pressure. With the use of a slit-valve, it is notnecessary to use an outlet check valve to prevent backflow.

Battery

An implantable battery used in an implantable pump of the presentinvention needs to be encapsulated to avoid harmful leaks and diffusion.Generally an implantable pump requires milliampere level current pulsesover a constant microampere level background drain. Examples ofcommercially available implantable batteries are lithium/thionylchloride and lithium/carbon mono fluoride batteries made by GreatBatch,EaglePicher Medical Power and other manufactures. A Li/CFx battery,which is typically used for pacemakers, neuro-stimulation applicationsat milliampere application ranges, has a typical lifetime of five to sixyears. A small implantable battery by EaglePicher achieves a miniaturecylindrical size of 0.260″ long×0.090″ diameter that can be packagedinside a pump device with a traditional implantation surgery orimplanted at a separate nearby location via a minimally-invasivecatheter procedure.

A preferred embodiment of a battery pack to be used for the presentinvention is a battery assembly comprising a first battery portion and asecond battery portion and a battery-low circuit for switching to thefirst battery portion for battery-low notification. The first batteryhas a higher capacity than the second battery with the voltage acrossthe first battery being greater than the voltage across the secondbattery. The battery assembly is connected to a pickup inductive coil inthe implantable drug delivery device, which can be charged by magneticflux produced by the inductive coil of an external battery chargeracross the skin. The battery pack includes a current limiting circuithaving a current limiting resistor for self-regulating and preventingovercharge. The implantations of the battery-low circuit and therecharging of the battery by induction means are well known in the skillof the art.

Pump Size

With the advancement of miniaturization technologies, small electricaland mechanical components as well as a concentrated drug formulation canbe packaged into a compact size for an implantable device of the presentinvention. For a commercially available piezoelectric motor, such asSQUIGGLE SQ-306 model by New Scale Inc., the motor size is 10 mm inlength and 4 mm in diameter. Its motor driver in an IC control boardincluding ASIC, resonant inductors, Boost circuit and FWD diodedeveloped by Austria Microsystems can be packaged into 10 mm×10 mm×1.5mm size. The motor can achieve a minimum linear shaft increment of 1micrometer. With a piston head of 4 mm diameter this minimum incrementof 1 micrometer movement results in the dispensing of 12.56 nano-litersfluid volume. With the capability of dispensing drug at the nano-literscale, the drug chamber size of the drug delivery device can beminimized utilizing the full potential of concentrated or nanoparticledrug formulations as well as for supplying significantly longer periodof use before refilling. Using other small components such as, a smallimplantable battery by EaglePicher which has a miniature cylindricalsize of 0.260″ long×0.090″ diameter, enables packaging the keycomponents of the drug delivery device into a compact system for implantapplications.

Notification Mode

For a given drug chamber size and a given infusion profile for apatient, the refill interval is known, therefore, the time to refill canbe planned. However, if refill does not occur in the appropriate timeinterval, a notification signal can be sent to the patient by theimplantable drug delivery device of this invention. The notificationfeature utilizes the reciprocating motion of the piston. The motordriver can be programmed for a notification mode. In notification modethe motor driver retracts the piston for a predetermined distance then,with the self-closing slit valve remaining at the closed position,performs a small reciprocating motion of the piston with amplitude notexceeding the retracted distance such that no amount of drug fluid isdispensed out of the slit valve. The amplitude and the frequency of thereciprocating motion are preset so as to generate a vibration of thedevice that does not cause any harm but is detectable by the patient.Conditions for the notification mode include the end of dispensing cyclefor refilling and battery low. For a predetermined battery low conditionthe built-in battery-low circuit in the control microprocessor triggersthe notification mode. As a reminder for the patient to refill thedevice the reciprocating motion may be repeated to signal at aprescribed interval, which is to be determined (TBD) for a patient usingthe device. For instance the notification mode or the oscillation of thepiston may be programmed to repeat at every 12 or 24 hours, depending onthe patient's dependency on the drug and other factors such as tocoincide with convenient day time schedules for taking action.

Verification

Additionally, there are a number of factors that may cause performancefailures of an implanted device. These factors include malfunction ofelectronics, hesitation in piston movement, voids in the drug reservoirand possible clogging at the dispensing opening. Therefore, anindependent verification of the performance of an implant device isessential to ensure reliable and predictable performance of the device.For verification of the pump performance of the present invention theposition of the piston or a residual amount of dispensing material inthe first chamber can be measured externally. As shown in FIG. 6cfollower 28A is fitted with a second magnet 76A and the displacement ofa magnet mounted on top of the follower can be determined by measuringthe distance 78A between the second magnet 76A and the first ring magnet92A, which is positioned at the center of the septum. The distancebetween two magnets can be measured by an external magnetic proximitysensor. A magnetic proximity sensor can be a commercially availableHoneywell HMC1501 or HMC1512 magneto-resistive sensors. These sensorsfeature Wheatstone bridge elements to convert a magnetic field into avoltage output. The HMC sensors provide reliable performance in accuracyand resolution.

Software Control Elements

The control software in the microprocessor controller of the presentinvention is programmed to provide Dispensing Mode, Refilling Mode,Notification Mode and Verification-Calibration Mode. In the DispensingMode, the microprocessor commands to provide pulses of differentdurations to control the dispensing rates depending on a prescribeddosage profile, which are converted into a set of operational parametersfor the operation of the motor driver. At each dispensing command, afterthe pre-determined forward pulses, a pre-determined number of backwardpulses follows to ensure positive-closing of the slit valve. Therequired number of backward pulses for closing the slit valve is lessthan the number of forward pulsed for dispensing such that the desirableamount of drug dosage is dispensed. The schedules and timings of thecontroller action are based on inputs from an IC oscillator timer builtin the IC board of the pump device. The IC circuit for an oscillatortimer is well known in the art. With an external controller, theoperational parameter set (OPS) in the implant pump of the presentinvention can be changed as needed. In addition a memory chip in thepump device records the history of forward and backward pulses. Analgorithm is provided in the control program to monitor the currentamount of drug remaining in the reservoir such that the timing forrefilling the reservoir is determined. The maximum travel distance ofthe piston between the reservoir full and reservoir empty is convertedinto the maximum number of dispensing pulses, which is pre-programmedwith a safety factor in the controller. When the maximum number ofdispensing pulses is reached, no further forward movement of the pistonis commanded.

In the Refilling Mode, upon trigging the refill switch by the insertionof the refill container needle, the controller microprocessor of thedevice of the present invention commands the motor driver to start thereciprocating motion of the piston. The duration of the refilling modeis preprogrammed for complete filling of the reservoir.

The Notification Mode can be programmed for repeated vibration of thepump device to alert the patient to take action to have the pump devicerefilled. The piston oscillation is initiated at the end of theDispensing Mode, therefore, no additional drug is dispensed from theslit valve at the Notification Mode. The reciprocation of the piston isoperated at detectable amplitude and frequency for a short duration suchas a few seconds. The objective is to create vibrations which do notcause any harm or discomfort to the patient but are adequate to alertthe patient to take action. At the Notification Mode, the command forthe oscillation motion of the piston is repeated over a time interval.

In the Verification-Calibration Mode, the control program of theinfusion pump of the present invention uses the input of a magneticproximity sensor to measure the distance between the two magnets in theimplant pump. The measured distance between the two magnets can beconverted to the amount of drug fluid remaining in the drug chamber andcompared to the expected value according to the prescribed dispensingdrug profile. The control software program maintains the prescribeddispensing drug profile for a patient for operation of the motor driver.For a specified drug dispensing profile and knowing the time from thestart of dispensing, the remaining amount of the drug fluid in thedevice can be determined, based on the geometry and size of the drugchamber, as an expected distance between the two magnets in the septumand in the piston. This expected distance is regarded as the expectedprofile value for comparing with the measured distance between the twomagnets. If at any time a discrepancy exists, the pump device can berefilled to full state and to record new starting time for the device.Such verification and calibration steps may be taken several times toensure the continuous use of the pump device according to the intendeddispensing profile. The verification-calibration mode should beconducted prior to a routine refilling action.

As a summary, FIG. 11 shows the interactions of the operation modes ofthe software control program of the implantable drug delivery pump ofthe present invention.

Although the invention has been described with reference to particularembodiments, the description is only an example of the invention'sapplication and should not be taken as a limitation. Various otheradaptations and combinations of features of the embodiments disclosedare within the scope of the invention. For example, a stepper motor maybe used as a drive means instead of a piezoelectric motor as describedin the present invention. Also, an external power source and externalcontroller may be used to reduce the size of an implantable pump deviceof the present invention. In such case the pump device needs to includean antenna and a RF receiver. Alternatively, a smaller size may beachieved by separating IC board and battery from the pump mechanism andimplanted at different location away from the basic pump mechanism.

Two-Drug-Chambers Device Configuration

An implantable dual drug delivery system of this invention features twodrug chambers with different refill container-port identifications formatching with correct refill containers of the two drugs. In thefollowing descriptions, first drug fluid and drug A fluid are usedinterchangeably. Second drug fluid and drug B fluid are usedinterchangeably. First chamber, drug A chamber and drug A reservoir areused interchangeably. External chamber, filler fluid chamber are usedinterchangeably.

Specifically an implantable dual drug infusion pump of the presentinvention has first drug chamber containing first drug fluid, seconddrug chamber containing second drug fluid and an external filler fluidchamber containing filler fluid. Each drug chamber is divided by a wallhaving a one-way valve into a first compartment and a secondcompartment. Each first compartment has a piston connected to a drivemeans and each second compartment has a follower, which is in flowcommunication with the movement of the piston.

The filler fluid chamber is attached externally to the drug chambers andit contains a filler fluid enclosed by collapsible soft layers. The softlayers are wrapped around housing walls of the drug chambers. The fillerfluid is in flow communication with both the first compartment and thesecond compartment of each drug chamber for filling the space left bythe movements of the pistons and the followers. Additionally, thepistons and the followers separate the filler fluid from the first drugfluid and the second drug fluid. The walls of the first and the secondchambers as well as that of the external chamber are impermeable tooutside fluids present in an operating environment.

Referring to FIGS. 12a, 12b and 12c , the dual drug delivery device ofthis invention comprises two independent drug chambers, drug chamber Aand drug chamber B, and one filler fluid chamber.

FIG. 12a shows drug A chamber 18B containing drug A20 having catheter44B with slit valve 52B and drug B chamber 18B′ containing drug B 20B′having catheter 44B′ with slit valve 52B′. These drug chambers andcatheters are oriented in opposite directions. Drug A chamber and drug Bchamber are of the same configuration and separated by a common ICcontrol board 32B and their housing walls 14B are attached with anexternal chamber 122B containing filler fluid 124B. The drive mechanismfor drug A piston 83B and drug B piston 83B′ are the same. Forsimplicity, only the drug chamber configuration and the drive mechanismfor drug A are described in FIG. 12c , which is a side cross-sectionview of the device of FIG. 12a . In FIG. 12a the drug A chamber 18B isdivided into first compartment 11B and second compartment 13B by a wall15B mounted with a one-way valve 17B.

FIG. 12b further shows a top cross-section view of the division betweenthe two compartments 11B and 13B by the wall 15B and the one-way valve17B for the drug A chamber, and the division between two compartments11B′ and 13B′ for the drug B chamber. Also shown in FIG. 12c is anextension of the dividing wall 15B and the one-way valve 17B into septum44B of the implant device 10B. In the enlarged view in FIG. 13, theflap-type one-way valve 17B provides a flow path 23B between the firstand the second compartments 11B and 13B when the valve 17B is in theopen position. The contact switch of electrodes 181B can be activated bythe insertion of the needle 85B, which also causes the blocking of thecatheter channel 49B. Alternatively, a plunger-type valve similar tothat shown in FIGS. 7c, 7d for a divided drug chamber can be used forclosing the flow path in the catheter channel by the insertion of theneedle of a refill container. The first compartment 11B has a piston 83Bconnected to a drive means and the second compartment 13B has a follower28B, which is in flow communication with the movement of the piston 83B.

Referring to FIG. 12c the external chamber 122B is segmented andattached externally to housing wall 14B. The external chamber 122B hasan external soft layer which is collapsible. The filler fluid 124B,which is inert to the drug fluids and body tissues, is in flowcommunication with the drug chambers for filling the space evacuated bythe movements of the piston and the follower to prevent creation of apartial vacuum that, if it were to exist, could negatively impact themovement of the pistons and the followers. Both piston 83B and follower28B (shown in FIG. 13) separate filler fluid 124B from drug fluid 20B.The piston is driven by a drive means for infusing the drug fluid Athrough outlet 34B and reducing the volume of the drug fluid A in thefirst compartment. The above descriptions for the chamber configurationand the movements of the piston and the follower for drug A areapplicable to that for drug B.

Moreover, referring to the drug A configuration, a catheter 48B isattached to outlet 341 of drug A chamber 18B in flow communication withthe drug fluid 20B. The wall 51B of the drug A chamber includes afilling septum 44B for inserting needle of a refill container to deliverrefill drug into the drug chamber. An outlet valve in a form ofslit-valve 52B is attached at the dispensing end of the catheter. Anormally-closed slit-valve prevents the backflow of fluids from theoutside environment into the device. The slit-valve is forced to open bythe forward movement of the piston exerting pumping pressure to forcethe drug exiting from the reservoir to the treatment site. Depending onthe geometry and the stiffness of the slit-valve elements, theslit-valve may be partially or fully open corresponding to the forwardsteps of the piston advancement. If the piston advancement is at aminimal number of steps the slit-valve may be partially open withoutdispensing the drug fluid out of the catheter,

Reciprocating Piston Motion

The piston performs a reciprocating motion under the control of aprogrammable motor driver which is mounted in IC control board 32B asshown in FIG. 12a . Each drug fluid is pushed by the forward movement ofits respective piston. The perimeter surface of each piston is inslidable sealing fit, represented by O-ring 61B, with the inner wallsurface of the first compartment 11B. The sliding-sealing fit or thewiping contact of the piston perimeter surface with the inner wall ofthe first chamber ensures no residual trace of drug fluid left behindthe piston that will come in contact with the filler fluid and similarlyno residual trace of the filler fluid left on the opposite side of thepiston that will contact with the drug fluid. During the forward motionof the piston the one-way valve is forced to close and the slit-valve atthe end of the catheter is forced to open to dispense the drug fluid.During the backward motion of the piston a partial vacuum is created inthe first compartment that causes the slit-valve to close and theone-way valve to open. As a result, referring to FIG. 12c , drug fluid20B from the second compartment 13B enters the first compartment 11Bthrough the valve opening 25B. Simultaneously, the follower 28B in thesecond compartment 13B moves forward.

The flow of the filler fluid 124B between the external chamber 122B andthe drug A chamber 18B is through first and second filler-fluid openings170B and 172B in housing walls as shown in FIG. 12b and FIG. 12c . Thefirst filler-fluid opening 170B on the first compartment wall 180B isfor the entrance and exit of the filler fluid 124B behind the piston 83Bas the piston moves forward and backward, respectively. On the otherhand, the second filler-fluid opening 172B on the second compartmentwall 182B is for the entrance and exit of the filler fluid behind thefollower 28B as the follower moves forward and backward, respectively,following the piston movement. The sliding-sealing fit or the wipingcontact of the follower perimeter surface with the inner wall of a drugchamber ensures no residual trace of drug fluid left behind the followerthat will come in contact with the filler fluid, and similarly noresidual trace of the filler fluid left on the opposite side of thefollower that will contact the drug fluid.

The filling of the filler fluid into drug A and drug B chambers reducesthe volume in the external filler fluid chamber, thereby causing thecollapsible soft layer 56B to contract. For a given drug dosage at eachinfusion event, the number of forward pulses and the immediate number ofbackward pulses can be predetermined for the device to provide thedesired net amount of drug dispensed at the event through theslit-valve. In subsequent repeated reciprocating motion of the piston,the drug fluid is incrementally dispensed and the follower is movingforward in each cycle. This process continues until the secondcompartment is empty. In the empty state, the space behind the followeris full of the filler fluid.

The dispensing process can start only when an activation detector isactivated. The permanent magnet 92B mounted on septum 44B as shown inFIG. 12c is attached with an internal magnet proximity sensor (notshown) to function as an activation detector for triggering thecontroller and the motor driver in control board 32B. The use of amagnet proximity sensor using Hall Effect for tuning the operationalgradient of the magnetic field normal to the face of the detector isknown in the art. Commercially magneto-resistive sensors of theHoneywell Company may be used as an activation detector. These sensorshave a high sensitivity with conventional magnets like AlNiCo andceramic materials and their Wheatstone bridge elements convert themagnetic field direction into a voltage output. Optionally, a ReedSensor of Cherry Corporation may be used as a magnetically activatedswitch. The internal magnet proximity sensor (not shown) is inelectrical communication with the motor driver and the microprocessor inthe IC board of the pump device. To save space in the septum area theHall Effect circuit of the magnet proximity sensor is integrated in theIC board 32B. When a specified starter-magnet, for activating the pumpdevice, is placed on top of the magnet ring 92B of the pump device 10Bacross the skin (not shown), the activation detector (not shown) detectsthe change of the magnetic field surrounding the magnet ring 92B and thecircuit of the proximity sensor converts the change of magnetic fieldinto a voltage output. The activation detector triggers the controllerand the motor driver to start the dispensing function of the pumpdevice.

Priming Steps

To avoid dead spaces, voids or air pockets in a dual-drug drug deliverydevice of the present invention, the priming steps for complete fillingof the device with drug A, drug B and filler fluid are as follows.Referring to a preferred embodiment as shown in FIGS. 16a, 16b and FIGS.15a, 15b for priming the drug A chamber with reference to components fordrug A and starting with a new and empty condition beforeimplantation, 1) squeeze and keep the slit valve in the open positionwhile moving follower 28B to the lower travel limit, i.e. the bottomhome position, 2) move piston 83B to the upper travel limit position, 3)insert an active-plunger syringe, pre-filled with the drug fluid to thetip of the needle, into septum 44B without opening one-way valve, 4)inject the drug fluid to fill the second compartment completely with anypossible air bubbles rising (not shown) against gravity in the septumcavity, 5) with the slit valve remaining open, push the syringe needlefurther to open the one-way valve, 5) inject drug fluid to fill theseptum and the catheter and expel the air through the slit valve, 6)release the slit valve to resume its self-closing position and retractthe piston to the lower travel limit to draw additional drug fluid fromthe syringe to fill the first compartment completely, 8.) remove thesyringe from the septum. To prime the drug B chamber with reference tocomponents for drug B, repeat above steps (1) to (8).

To prime the filler fluid chamber, with both the drug A and drug Bchambers totally filled, 1) insert an active-plunger filler fluidsyringe needle into the injection port of the filler fluid chamber atthe gap below the follower, 2) insert vent needles through the wall ofthe filler fluid chamber at the extreme opposite location of theinjection flow path of the filler fluid from the filler fluid injectionport to vent air, 3) inject the filler fluid to fill the filler fluidchamber completely and expel the air through the vent needles untilfluid exits the vent, 4) remove the filler fluid syringe and the ventneedles. Alternatively, the evacuation of the air can be facilitated bya vacuum means attached to the vent needle during the injection of thefiller fluid into the chamber. In addition, the wall areas for insertingthe vent needle and the filler fluid syringe needle are of resilientmaterial, which is penetrable and self-closing when the needles areremoved. After the above priming steps the device is completely filledwith the drug A in the drug A chamber, drug B in the drug B chamber andthe filler fluid in the filler fluid chamber without any dead spaces,voids or air pockets in the device.

Refilling Process

FIGS. 14a, 14b, 14c, 14d show a sequence of the refilling process ofdevice 10B including the contraction and expansion of the external softlayer 56B containing the filler fluid 124B. FIG. 14a shows animplantable dual drug delivery device 10B as described in FIG. 12c atthe full state with both the piston and the follower at their homepositions. The home position of the follower is the lower travel limitof the follower. A forward movement as indicated by the arrow 160B ofthe piston 83B toward the slit-valve 52B causes the slit-valve to openunder the pumping pressure. After repeated forward and backwardmovements of the piston the second compartment 13B is depleted with drugA fluid 20B but filled with filler fluid 124B behind the follower 28B asshown in FIG. 14b . The top end of the second compartment is the uppertravel limit of the follower. For refilling, a needle 185B of refillcontainer 184B with refill drug A 137B is inserted into the septum 44Bof device 10B as shown in FIG. 14c . Correct positioning of the refillcontainer enables the needle to push open the one-way valve 17B towardthe catheter wall. Further pushing of the needle 185B forces thecatheter walls 149B to close and block the flow of the drug A fluid intothe catheter. Contacting of the catheter walls also enables the contactof two thin electrode elements 181B, which are in electricalcommunication with the motor driver in IC control board 32B, to activatethe reciprocating motion of the piston 83B. During retraction orbackward movement 162B of the piston as shown in FIG. 14c only therefill drug A inside the refill container, which is compacted byslidable disc 185B at atmospheric pressure due to the presence of ventopening 186B, is drawn into the first compartment while the refill drugA inside the second compartment is held back by a partial vacuum as thedevice is enclosed by body tissues. The next subsequent forward movementof the piston pushes the first fluid into the second compartment,similar to flow path 23B in FIG. 13a , through the edges of the one-wayvalve opening. A series of such reciprocating pumping motions can drawin the filler fluid 124B from the soft-layer external chamber 122Bthrough the first and second filler-fluid openings to fill the spacebehind the piston and the follower. At the completion of a refillingprocess as shown in FIG. 14d indicating an empty refill container 184Bthe piston and the follower are at their home positions and that thesoft-layer chamber is at its fully expanded shape. Note that the refillcontainer is of a “passive type” having no plunger thereby avoiding anyaccidental injection. Infusion from the refill container is possibleonly by the pumping action of the piston.

Failsafe Refill Container Feature

The refilling of the dual drug delivery device of the present inventionpreferably uses self-locking refill containers to prevent the injectionof drug into the wrong drug chamber. To ensure the correct matching of adrug refill container with the septum of the same drug, magnets ofopposite polarities are used to create an attraction force between thematched refill container and the septum. With a mismatched refillcontainer and septum, a repelling force is created that locks the refillcontainer. For clarity, a magnet of a septum of drug A chamber is usedfor illustration in FIG. 15a and FIG. 15b . The magnet is preferably aring magnet which is hollow at the center for inserting the needle ofthe refill container through the septum. FIG. 15a shows attraction force230B between the matched refill container A 284B and magnet 92B of theseptum of the drug chamber for drug A. As a result, magnet 260B of therefill container is attracted to the magnet 92B of drug A chamber 18B,therefore, opening the flow path, as shown in FIG. 16a , from thereservoir 237B to drug chamber 18B.

The self-locking refill container 284B comprises a needle 285B, atubular housing containing drug fluid 237B. The tubular housing includesa valve chamber 262B having an open end 261 B in communication withneedle 285B and a reservoir chamber 264B which is attached with aslidable disc 289B forming an enclosed bottom. An orifice plate 240B ispositioned between and separating valve chamber 262B and reservoirchamber 264B. Orifice plate 240B has orifice 255B at the center forpassage of the drug fluid from the reservoir chamber to the valvechamber. The drug fluid is compacted by the slidable disc, which is atatmospheric pressure due to the presence of vent opening 291B. In apreferred embodiment the movable magnet 260B is an annular ringconfiguration. The annular magnet ring 260B has a top surface having asolid block area 252B in the center and a plurality of slot openings250B surrounding the center block area 252B. The annular magnet ring260B has a polarity that is opposite to the ring magnet 92B of theseptum of the same drug such that the annular ring 260B is attractedaway from the orifice plate 240B when the needle of the refill containeris inserted into the septum of the correct drug chamber. When the topsurface of the annular magnet ring is away from the orifice plate, aflow path is created for the drug fluid to be drawn into the drugchamber.

FIG. 15b shows a repelling force 232B between a mismatched refillcontainer 284B′ of drug B and ring magnet 92B of the septum of drug Achamber. The refill container 284B′ of drug B has the same configurationas that of the refill container 284B of drug A except that the polarityof its annular magnet with refill drug A 137B is inserted into theseptum 44 B of device 10B as shown in FIG. 14c . When needle 285B′ ofthe refill container is inserted into the septum of drug A, its annularring is repelled toward the orifice plate 240B′ such that the solidblock area 252B′ completely blocks the opening of the orifice plate240B′. As a result, the refill container of drug B is locked as the flowof the drug is blocked from flowing into the drug chamber A. All thering magnet valves used in the refill container are to be coated with aninert, biomedical and drug compatible material to prevent reaction withthe drugs delivered by the device.

Matched Filling Condition

A matched refilling condition is shown in FIG. 16a and FIG. 16b . FIG.16a shows an implantable dual drug delivery device 10B of the presentinvention in which the polarity of the ring magnet 260B of the refillcontainer 284B of drug A 237B is opposite to that of the septum ringmagnet 928 of drug A chamber 18B. Due to the attraction force 230Bbetween the two ring magnets 92B and 260B, the refill container 284B isunlocked internally when inserted into the septum. The contact of twoelectroplates 181B pushed by the refill container needle activates themotor driver in the IC control board 32B to start reciprocating motionof the piston 28B. The internal mechanism of refilling is as describedpreviously on FIG. 14c and FIG. 14d . The refilling stops when therefill container A 284 B becomes empty 238B as shown in FIG. 16b or whenthe reciprocating motion of the piston reaches a predetermined timeinterval according to the software control program. FIG. 16b also showsthat the soft layer 56B of the filler fluid 124B has been expanded fullyand the refill container being removed from the septum.

In a mis-matched condition, FIG. 17a shows a dual drug delivery device10B of the present invention being inserted with a refill container 284Bof drug A into the septum 44 b′ of drug B chamber 18B′, as indicated inFIG. 12a . In this case the polarity of the annular ring magnet of therefill container is the same as that of the septum. Therefore, theannular ring magnet ring 260B is repelled blocking the opening 255B inthe base plate. As a result, the refill container 284B is internallylocked so that the flow from the refill container is prevented. Withcorrect matching, refill container 284B′ of drug B 237B′ should be usedand the polarity of its annular ring magnet is opposite to ring magnet92B′ of septum 44B′ of drug B as shown in FIG. 17b . FIG. 17c shows thecompletion of the refilling of drug B as the refill container 284B′ isbeing removed from the septum 44B′.

Two Drug Chambers of Same Orientation

In the forgoing descriptions, two drug chambers and their catheters arealigned in opposite directions. Also, alternatively, each drug chambermay not be divided into two compartments by a wall having a one-wayvalve. FIG. 18a and FIG. 18b show an implantable dual drug delivery pumpdevice 700B of the present invention having two drug chambers 718B and718 b and their catheters 748B and 748B′ aligned in the same direction.Drug A chamber 718B and drug B3 chamber 718B′ contain drug A 720B anddrug B 720B′, respectively, and each drug chamber is undivided. FIG. 18bis a top view from a cross-section showing spatial arrangement of thedrug chambers 718B and 718B′. The pistons 783B and 783B′ in the chambersare driven by motors 736B and 736B′, which are driven by a common motordriver in the IC control board 732B. The operation of each drug chamberof the dual drug delivery device as shown in FIG. 18a is similar to thatof dual-drugs delivery device having an opposite orientation as shown inFIG. 12a . However, the dispensing and the refilling actions for anundivided drug chamber 718B without using an internal one-way valve aresimpler than that for a divided drug chamber 18B of FIG. 2a . For anundivided drug chamber configuration no reciprocating motion is requiredfor piston movement to effect dispensing and refilling actions. Pistons736B and 736B′ are driven independently forward for pre-determinednumber of steps to dispense the desirable drug dosage until the drugreservoir is empty. For refilling, after a refill container of the samedrug is inserted, activating the contact switch for the piston of thesame drug chamber, then the piston is automatically retracted to drawthe refill drug fluid into the drug chamber until the drug chamber isfull. Simultaneously the filler fluid 724B fills the space behind thepiston during the dispensing mode and leaves the space during therefilling mode. Following the movement of the filler fluid the softlayer 756B of the filler fluid chamber contracts and expands in thedispensing mode and the refilling mode, respectively. In comparison withthe divided drug chamber configuration, the minimum amount of drug fluiddispensed per piston advancement is higher than that of the undividedconfiguration. The selection of divided or undivided drug chamberdepends on drug concentrations, frequency of infusion and the sizelimitation of the dual-drug pump device.

Ultrasonic Motor

A drive means of an implantable infusion delivery device of the presentinvention can be a threaded rod 81B driven by motor 36B as illustratedin FIG. 12a . The rotation of threaded rod 81B causes forward andbackward movements of piston 83B corresponding to the rotationaldirection of the motor. Preferably motor 36B is a piezoelectric motor,which is illustrated in FIG. 12a comprising threaded rod 81B andpiezoelectric plates (not shown) with one end forming a threaded-nutconfiguration (not shown). The vibration of the piezoelectric plates cancause the threaded rod to rotate. Threaded rod 81B is in free-to-rotateengagement with the piston 28B. Generally the piston may havenon-circular cross-section undergoing linear movement without rotation.The conversion of rotational motion of thread rod 81B to linear motionof the piston is achieved by using a rotational sleeve and a retainer.

Materials of Device Components

Referring to FIG. 12a , walls 52B of the first chamber and collapsiblesoft layer 56B of and the filler fluid chamber are impermeable toexternal fluids present in a living tissue environment. In particular,walls 52B of drug chambers are made of a drug-compatible, implantablematerial of sufficient rigidity without deformation so as not to hinderthe movement of piston inside the reservoir chamber. For example, thewall material of the drug chambers may be constructed from a metal, suchas titanium, nickel titanium, stainless steel, anodized aluminum, ortantalum, or a plastic, such as polyethylene, nylon, or polyurethane.However, soft layer wall 56B of filler fluid chamber 122B is made offlexible material such as silicone, or polyurethane, which allows thewall to expand or collapse as fluid is added or withdrawn from the firstchamber into the filler fluid chamber. For self-sealing the septum ismade of resilient material. Preferably PDMS is selected for itsflexibility and ability to reseal itself after repeated punctures via arefill container needle.

In implantation, a drug delivery device is implanted near the treatmentsite and the slit-valve is to be located at the treatment site. In apreferred embodiment positive-closing slit-valve 52B is a moldeddome-shaped cap of elastomeric materials having a cross-slit cut forminga plurality of flexible flappers. In a preferred embodiment a slit-valveused for the implantable infusion pump of this invention is ofbiocompatible silicone material. The slit-valve has a tubular wall baseand four flappers. Each flapper is a curved triangular valve segmentextending from the tubular wall base with tip of each valve segmentintercepting at the center, i.e. at the apex of the slit-valve openingwhen the slit-valve is at the closed position. Each valve segment can bebent like a cantilever beam under the pressure of a dispensing flow. Theslit length, wall thickness and the elastic modulus of the valvematerial are designed to ensure self-closing of the slit-valve by theresiliency and the vacuum force at the absence of pumping pressure. Withthe use of a slit-valve, it is not necessary to use an outlet checkvalve for preventing backflow.

Software Control Elements

The control software in the microprocessor controller of the presentinvention is programmed to provide Dispensing Mode, Refilling Mode,Anti-Clogging Mode, Notification Mode and Verification-Calibration Mode.In the Dispensing Mode, the microprocessor commands for dispensing drugA and drug B are independent. For each drug the microprocessor sendscommands to provide pulses of different durations for controlling thedispensing rates depending on a prescribed dosage profile and schedulefor the drug, which are converted into a set of operational parametersfor the operation of the motor driver for the drug. At each dispensingcommand, after the pre-determined forward pulses, a pre-determinednumber of backward pulses follow to ensure positive-closing of theslit-valve. The required number of backward pulses for closing theslit-valve is less than the number of forward pulses for dispensing suchthat the desirable amount of drug dosage is dispensed. The schedules andtimings of the controller action are based on inputs from an ICoscillator timer built in the IC board of the pump device. The ICcircuit for an oscillator timer is well known in the art. With anexternal controller, the operational parameter set (OPS) in the implantdevice of the present invention can be changed when the need of thepatient changes. In addition a memory chip in the device records historyof forward and backward pulses for each drug. An algorithm is providedin the control program to monitor the current amount of drug remainingin each drug chamber such that the timing for refilling each of the twodrug chambers is determined. The maximum travel distance of the pistonin a drug chamber in between the chamber full and chamber empty isconverted into the maximum number of dispensing pulses, which ispre-programmed with a safety factor in the controller. When the maximumnumber of dispensing pulses is reached, no further forward movement ofthe piston is commanded.

In the Refilling Mode, upon triggering the refill switch by theinsertion of a refill container needle in the septum of a drug chamber,the controller microprocessor of the device of the present inventioncommands the motor driver to start the reciprocating motion of thepiston in the drug chamber. The duration of the refilling mode ispre-programmed for complete filling of the drug chamber.

The Notification Mode can be programmed for repeated vibration of thepump device to alert the patient to take action to have the pump devicerefilled. The piston oscillation is initiated at the end of theDispensing Mode, therefore, no additional drug is dispensed from theslit valve at the Notification Mode. The reciprocation of the piston isoperated at detectable amplitude and frequency for a short duration suchas a few seconds. The objective is to create vibrations which do notcause any harm or discomfort to the patient but are adequate to alertthe patient to take action. At the Notification Mode, the command forthe oscillation motion of the piston is repeated over a time interval.

In the Verification-Calibration Mode, the control program of the dualinfusion pump of the present invention uses the input of a magneticproximity sensor which measures the distance between the two magnets ineach drug chamber. The measured distance between the two magnets can beconverted to the amount of drug fluid remaining in the drug chamber andcompared to the expected value according to the prescribed dispensingdrug profile. The control software program maintains the prescribeddispensing drug profile for a patient for the operation of the motordriver. For a specified drug dispensing profile and knowing the timefrom the start of dispensing, the remaining amount of the drug fluid inthe device can be determined, based on the geometry and size of the drugchamber, as an expected distance between the two magnets in the septumand in the piston. This expected distance is regarded as the expectedprofile value for comparison with the measured distance between the twomagnets. If at any time a discrepancy exists, each drug chamber of thedual pump device can be refilled to full state and a new starting timerecorded for the device. Such verification and calibration steps may betaken several times to ensure the continuous use of the dual pump devicefollows the intended dispensing profile. The verification-calibrationmode should be conducted prior to a routine refilling action.

As a summary, FIG. 19 shows the interactions of the operation modes ofthe software control program of the implantable drug delivery pump ofthe present invention.

Although the invention has been described with reference to particularembodiments, the description is only an example of the invention'sapplication and should not be taken as a limitation. Various otheradaptations and combinations of features of the embodiments disclosedare within the scope of the invention.

We claim:
 1. A refill container for refilling an implantable drugdelivery device comprising: a. a tubular housing with inner wall surfacehaving first opening and second opening, said tubular housing containinga drug fluid, b. a needle being attached to the second opening, saidneedle being in flow communication with the tubular housing, c. a discsituated inside said tubular housing in slidable sealing fit with aninner wall surface, said disc not accessible from outside the housingand being only movable following the flow direction toward the needlewhen the drug fluid is being removed from the housing through theneedle, said disc being exposed to ambient pressure through the firstopening.
 2. The refill container according to claim 1, wherein saidtubular housing comprises a valve chamber situated at said secondopening end and a reservoir chamber situated at said first opening end,and further comprising an orifice plate being positioned separating thevalve chamber and the reservoir chamber, said orifice plate having anorifice at the center for passing a drug fluid from the reservoirchamber to the valve chamber, and said valve chamber includes a movablemagnet valve having a polarity being situated in said valve chamber suchthat said magnet valve blocks the opening of the orifice plate whenmoved in contact with the orifice plate and allows for the flow of thedrug fluid from the reservoir chamber to the needle when said magnetvalve is moved away from the orifice plate.
 3. A refill system of animplantable dual drug delivery device comprising: a. a first refillcontainer containing a first drug fluid having a magnet valve with afirst polarity, b. a second refill container containing a second drugfluid having a magnet valve with a second polarity, c. a first drugchamber containing a first drug fluid and having an outlet, a septum anda first piston, said septum being attached with a first magnet withfirst polarity attracting the magnet valve of the first refill containerand repelling the magnet valve of the second refill container, d. asecond drug chamber containing a second drug fluid and having an outlet,a septum and a second piston, said septum being attached with a secondmagnet with second polarity attracting the magnet valve of the secondrefill container, said second polarity being opposite to the firstpolarity of said first refill container.